IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression.

Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language processing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes. IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid. It associates with reduced survival in glioma patients, promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice. Immune checkpoint blockade (ICB) induces IDO1 and IL4I1. As IDO1 inhibitors do not block IL4I1, IL4I1 may explain the failure of clinical studies combining ICB with IDO1 inhibition. Taken together, IL4I1 blockade opens new avenues for cancer therapy.

Immune Characteristics and Immunotherapy of HIV-Associated Lymphoma.

In the era of antiretroviral therapy (ART), mortality among people living with the human immunodeficiency virus (HIV) has significantly decreased, yet the population of people living with HIV remains substantial. Among people living with HIV (PLWH), HIV-associated lymphoma (HAL) has surpassed Kaposi's sarcoma to become the most common tumor in this population in developed countries. However, there remains a dearth of comprehensive and systematic understanding regarding HIV-associated lymphomas. This review aims to shed light on the changes in the immune system among PLWH and the characteristics of the immune microenvironment in HIV-associated lymphoma, with a specific focus on the immune system's role in these individuals. Additionally, it seeks to explore recent advancements in immunotherapy for the treatment of HIV-associated lymphoma, intending to enhance strategies for immunotherapy in this specific population.

Cellular and micro-environmental responses influencing the antitumor activity of all-trans retinoic acid in breast cancer.

All-trans retinoic acid (ATRA) is the most relevant and functionally active metabolite of Vitamin-A. From a therapeutic standpoint, ATRA is the first example of pharmacological agent exerting its anti-tumor activity via a cell differentiating action. In the clinics, ATRA is used in the treatment of Acute Promyelocytic Leukemia, a rare form of myeloid leukemia with unprecedented therapeutic results. The extraordinary effectiveness of ATRA in the treatment of Acute Promyelocytic Leukemia patients has raised interest in evaluating the potential of this natural retinoid in the treatment of other types of neoplasias, with particular reference to solid tumors.The present article provides an overview of the available pre-clinical and clinical studies focussing on ATRA as a therapeutic agent in the context of breast cancer from a holistic point of view. In detail, we focus on the direct effects of ATRA in breast cancer cells as well as the underlying molecular mechanisms of action. In addition, we summarize the available information on the action exerted by ATRA on the breast cancer micro-environment, an emerging determinant of the progression and invasive behaviour of solid tumors. In particular we discuss the recent evidences of ATRA activity on the immune system. Finally, we analyse and discuss the results obtained with the few ATRA-based clinical trials conducted in the context of breast cancer.

Non-Coding RNA in Tumor Cells and Tumor-Associated Myeloid Cells-Function and Therapeutic Potential.

The RNA world is wide, and besides mRNA, there is a variety of other RNA types, such as non-coding (nc)RNAs, which harbor various intracellular regulatory functions. This review focuses on small interfering (si)RNA and micro (mi)RNA, which form a complex network regulating mRNA translation and, consequently, gene expression. In fact, these RNAs are critically involved in the function and phenotype of all cells in the human body, including malignant cells. In cancer, the two main targets for therapy are dysregulated cancer cells and dysfunctional immune cells. To exploit the potential of mi- or siRNA therapeutics in cancer therapy, a profound understanding of the regulatory mechanisms of RNAs and following targeted intervention is needed to re-program cancer cells and immune cell functions in vivo. The first part focuses on the function of less well-known RNAs, including siRNA and miRNA, and presents RNA-based technologies. In the second part, the therapeutic potential of these technologies in treating cancer is discussed, with particular attention on manipulating tumor-associated immune cells, especially tumor-associated myeloid cells.

Signal conversion as tumor micro environment (TME) specifically activated cytokine.

Targeted cytokine delivery has been gaining popularity in cancer immunotherapy since systemic recombinant cytokine treatment has not been successful due to low response rate and systemic toxicities in the clinical studies. In order to address these issues, we propose a new concept that cytokine signal is specifically activated at tumor-micro-environment (TME) by delivering two protein subunits of heterodimeric cytokine fused with a tumor targeting antibody respectively to TME and by bridging the two subunits into active heterodimeric form.Interleukin-12 (IL-12) is one of the major cytokines which can induce immune activation. IL-12 consists of two protein subunits which are p35 and p40. IL-12 signaling is initiated when it forms as the heterodimeric protein and binds to IL-12 receptor complex. We made fusion proteins of both IL-12p35 and IL-12p40 targeting specific tumor associated antigens (TAAs) and demonstrated the formation of bioactive IL12p70 with TME targeting antibody toward both p35 and p40 to form as the active molecule. We describe our concept validation in an in vitro based functional assay.

Bruton tyrosine kinase inhibitors preserve anti-CD19 chimeric antigen receptor T-cell functionality and reprogram tumor micro-environment in B-cell lymphoma.

BACKGROUND AIMS: Combination therapy is being actively explored to improve the efficacy and safety of anti-CD19 chimeric antigen receptor T-cell (CART19) therapy, among which Bruton tyrosine kinase inhibitors (BTKIs) are highly expected. BTKIs may modulate T-cell function and remodel the tumor micro-environment (TME), but the exact mechanisms involved and the steps required to transform different BTKIs into clinical applications need further investigation. METHODS: We examined the impacts of BTKIs on T-cell and CART19 phenotype and functionality in vitro and further explored the mechanisms. We evaluated the efficacy and safety of CART19 concurrent with BTKIs in vitro and in vivo. Moreover, we investigated the effects of BTKIs on TME in a syngeneic lymphoma model. RESULTS: Here we identified that the three BTKIs, ibrutinib, zanubrutinib and orelabrutinib, attenuated CART19 exhaustion mediated by tonic signaling, T-cell receptor (TCR) activation and antigen stimulation. Mechanistically, BTKIs markedly suppressed CD3-ζ phosphorylation of both chimeric antigen receptor and TCR and downregulated the expression of genes associated with T-cell activation signaling pathways. Moreover, BTKIs decreased interleukin 6 and tumor necrosis factor alpha release in vitro and in vivo. In a syngeneic lymphoma model, BTKIs reprogrammed macrophages to the M1 subtype and polarized T helper (Th) cells toward the Th1 subtype. CONCLUSIONS: Our data revealed that BTKIs preserved T-cell and CART19 functionality under persistent antigen exposure and further demonstrated that BTKI administration was a potential strategy for mitigating cytokine release syndrome after CART19 treatment. Our study lays the experimental foundation for the rational application of BTKIs combined with CART19 in clinical practice.

[When a metastasis hides another]. / Quand une métastase en cache une autre.

Breast cancer is one of the leading causes of death in women. There are many different entities, both morphologically and immuno-histochemically or genomically. Intra-tumour heterogeneity can be defined in time (temporal heterogeneity) and in space (spatial heterogeneity) and is influenced by both internal and external factors, such as genetics, epigenetics, host response, possible treatments or the tumour microenvironment. The detailed analysis of these multiple interactions could help to develop new therapeutic targets.

Le cancer du sein est l'une des premières causes de décès chez les femmes. Il existe de nombreuses entités différentes, tant sur le plan morphologique que sur le plan immuno-histochimique ou encore génomique. L'hétérogénéité intra-tumorale peut être définie dans le temps (hétérogénéité temporelle) et dans l'espace (hétérogénéité spatiale) et influencée par des facteurs tant internes qu'externes tels que la génétique, l'épigénétique, la réponse de l'hôte, les éventuels traitements administrés, ou encore le micro-environnement tumoral. L'analyse approfondie de ces multiples interactions pourrait aider à développer de nouvelles cibles thérapeutiques.

Nanoparticle mediated cancer immunotherapy.

The versatility and nanoscale size have helped nanoparticles (NPs) improve the efficacy of conventional cancer immunotherapy and opened up exciting approaches to combat cancer. This review first outlines the tumor immune evasion and the defensive tumor microenvironment (TME) that hinders the activity of host immune system against tumor. Then, a detailed description on how the NP based strategies have helped improve the efficacy of conventional cancer vaccines and overcome the obstacles led by TME. Sustained and controlled drug delivery, enhanced cross presentation by immune cells, co-encapsulation of adjuvants, inhibition of immune checkpoints and intrinsic adjuvant like properties have aided NPs to improve the therapeutic efficacy of cancer vaccines. Also, NPs have been efficient modulators of TME. In this context, NPs facilitate better penetration of the chemotherapeutic drug by dissolution of the inhibitory meshwork formed by tumor associated cells, blood vessels, soluble mediators and extra cellular matrix in TME. NPs achieve this by suppression, modulation, or reprogramming of the immune cells and other mediators localised in TME. This review further summarizes the applications of NPs used to enhance the efficacy of cancer vaccines and modulate the TME to improve cancer immunotherapy. Finally, the hurdles faced in commercialization and translation to clinic have been discussed and intriguingly, NPs owe great potential to emerge as clinical formulations for cancer immunotherapy in near future.

The soluble form of CD160 acts as a tumor mediator of immune escape in melanoma.

Melanoma is responsible for 90% of skin cancer-related deaths. Major therapeutic advances have led to a considerable improvement in the prognosis of patients, with the development of targeted therapies (BRAF or MEK inhibitors) and immunotherapy (anti-CTLA-4 or -PD-1 antibodies). However, the tumor constitutes an immunosuppressive microenvironment that prevents the therapeutic efficacy and/or promotes the development of secondary resistances. CD160 is an activating NK-cell receptor initially described as delineating the NK and CD8+ T-cell cytotoxic populations. Three forms of CD160 have been described: (1) the GPI isoform, constitutively expressed and involved in the initiation of NK-cells' cytotoxic activity, (2) the transmembrane isoform, neo-synthesized upon cell activation, allowing the amplification of NK cells' cytotoxic functions and (3) the soluble form, generated after cleavage of the GPI isoform, which presents an immuno-suppressive activity. By performing immunohistochemistry analyses, we observed a strong expression of CD160 at the primary cutaneous tumor site of melanoma patients. We further demonstrated that melanoma cells express CD160-GPI isoform and constitutively release the soluble form (sCD160) into the tumor environment. sCD160 was shown to inhibit the cytotoxic activity of NK-cells towards their target cells. In addition, it was found in the serum of melanoma patients and associated with increased tumor dissemination. Altogether these results support a role for sCD160 in the mechanisms leading to the inhibition of anti-tumor response and immune surveillance in melanoma.

Biomaterials for Mimicking and Modelling Tumor Microenvironment.

This chapter summarizes the current biomaterials and associated technologies used to mimic and characterize the tumor microenvironment (TME) for developing preclinical therapeutics. Research in conventional 2D cancer models systematically fails to provide physiological significance due to their discrepancy with diseased tissue's native complexity and dynamic nature. The recent developments in biomaterials and microfabrication have enabled the popularization of 3D models, displacing the traditional use of Petri dishes and microscope slides to bioprinters or microfluidic devices. These technologies allow us to gather large amounts of time-dependent information on tissue-tissue, tissue-cell, and cell-cell interactions, fluid flows, and biomechanical cues at the cellular level that were inaccessible by traditional methods. In addition, the wave of new tools producing unprecedented amounts of data is also triggering a new revolution in the development and use of new tools for analysis, interpretation, and prediction, fueled by the concurrent development of artificial intelligence. Together, all these advances are crystalizing a new era for biomedical engineering characterized by high-throughput experiments and high-quality data.Furthermore, this new detailed understanding of disease and its multifaceted characteristics is enabling the long searched transition to personalized medicine.Here we outline the various biomaterials used to mimic the extracellular matrix (ECM) and redesign the tumor microenvironment, providing a comprehensive overview of cancer research's state of the art and future.

Delivery of siHIF-1α to Reconstruct Tumor Normoxic Microenvironment for Effective Chemotherapeutic and Photodynamic Anticancer Treatments.

The tumor hypoxic microenvironment not only induces genetic and epigenetic changes in tumor cells, immature vessels formation for oxygen demand, but also compromises the efficiency of therapeutic interventions. On the other hand, conventional therapeutic approaches which kill tumor cells or destroy tumor blood vessels to block nutrition and oxygen supply usually facilitate even harsher microenvironment. Thus, simultaneously relieving the strained response of tumor cells and blood vessels represents a promising strategy to reverse the adverse tumor hypoxic microenvironment. In the present study, an integrated amphiphilic system (RSCD) is designed based on Angiotensin II receptor blocker candesartan for siRNA delivery against the hypoxia-inducible factor-1 alpha (HIF-1α), aiming at both vascular and cellular "relaxation" to reconstruct a tumor normoxic microenvironment. Both in vitro and in vivo studies have confirmed that the hypoxia-inducible HIF-1α expression is down-regulated by 70% and vascular growth is inhibited by 60%. The "relaxation" therapy enables neovascularization with more complete and organized structures to obviously increase the oxygen level inside tumor, which results in a 50% growth inhibition. Moreover, reconstruction of tumor microenvironment enhances tumor-targeted drug delivery, and significantly improves the chemotherapeutic and photodynamic anticancer treatments.

The value of a new prognostic model developed by lymphocyte-monocyte ratio and platelet-monocyte ratio in peripheral T-cell lymphoma.

Peripheral T-cell lymphoma(PTCL) is a group of lymphoproliferative tumors originated from post-thymic T cells or mature natural killer (NK) cells. It shows highly aggressive clinical behaviour, resistance to conventional chemotherapy, and a poor prognosis. Although a few prognostic models of PTCL have been established in retrospective studies, some high-risk patients still can not be screened out. Therefor we retrospectively studied 347 newly diagnosed PTCL patients and assessed the prognostic role of lymphocyte-monocyte ratio (LMR) and platelet-monocyte ratio (PMR) in the complete response (CR) and survival of PTCL patients. Patients with LMR ≤ 1.68 and PMR ≤ 300 achieved a lower CR rate and a poor survival. In multivariate analysis, LMR ≤ 1.68 (HR = 1.751, 95% CI 1.158-2.647, p < 0.05) and PMR ≤ 300 (HR = 1.762, 95% CI 1.201-2.586, p < 0.05) were independently associated with short survival. On this basis, a new prognostic model of PTCL was established to screen out high-risk patients. In our "Peripheral Blood Score (PBS)" model, three groups were identified at low risk (178 patients, 51.3%, score 0), intermediate risk (85 patients, 24.5%, score 1), and high risk (84 patients, 24.2%, score 2), having a 1-year OS of 86%, 55.3% and 22.6% (p < 0.05), and a 3-year OS of 43.4%, 20% and 13.1% (p < 0.05), respectively. Optimal strategies for identifying high-risk patients with PTCL are urgently needed. Our new PBS model is simple, inexpensive and widely available to screen out the high risk patients.

23 Na-MRI as a Noninvasive Biomarker for Cancer Diagnosis and Prognosis.

The influx of sodium (Na+ ) ions into a resting cell is regulated by Na+ channels and by Na+ /H+ and Na+ /Ca2+ exchangers, whereas Na+ ion efflux is mediated by the activity of Na+ /K+ -ATPase to maintain a high transmembrane Na+ ion gradient. Dysfunction of this system leads to changes in the intracellular sodium concentration that promotes cancer metastasis by mediating invasion and migration. In addition, the accumulation of extracellular Na+ ions in cancer due to inflammation contributes to tumor immunogenicity. Thus, alterations in the Na+ ion concentration may potentially be used as a biomarker for malignant tumor diagnosis and prognosis. However, current limitations in detection technology and a complex tumor microenvironment present significant challenges for the in vivo assessment of Na+ concentration in tumor. 23 Na-magnetic resonance imaging (23 Na-MRI) offers a unique opportunity to study the effects of Na+ ion concentration changes in cancer. Although challenged by a low signal-to-noise ratio, the development of ultrahigh magnetic field scanners and specialized sodium acquisition sequences has significantly advanced 23 Na-MRI. 23 Na-MRI provides biochemical information that reflects cell viability, structural integrity, and energy metabolism, and has been shown to reveal rapid treatment response at the molecular level before morphological changes occur. Here we review the basis of 23 Na-MRI technology and discuss its potential as a direct noninvasive in vivo diagnostic and prognostic biomarker for cancer therapy, particularly in cancer immunotherapy. We propose that 23 Na-MRI is a promising method with a wide range of applications in the tumor immuno-microenvironment research field and in cancer immunotherapy monitoring. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Cancer-Associated Fibroblasts in Conversation with Tumor Cells in Endometrial Cancers: A Partner in Crime.

A tumor cell carrying characteristic genomic alteration(s) exists within its host's microenvironment. The tumor microenvironment (TME) renders holistic support to the tumor via cross-talk between tumor cells and three components of TME, immune components, vascular components, and fibroblast components. The tempero-spatial interaction of tumor cells with its microenvironment is the deterministic factor for tumor growth, progression, resistance to therapy, and its outcome in clinics. TME (1) facilitates proliferation, and the ensuing metastasis-associated phenotypes, (2) perturbs immune surveillance and supports tumor cells in their effort to evade immune recognition, and (3) actively participates in developing drug-induced resistance in cancer cells. Cancer-Associated Fibroblast (CAF) is a unique component of TME. CAF is the host mesenchyme immediately surrounding the tumor cells in solid tumors. It facilitates tumor growth and progression and participates in developing drug resistance in tumor cells by playing a critical role in all the ways mentioned above. The clinical outcome of a disease is thus critically contributed to by the CAF component of TME. Although CAFs have been identified historically, the functional relevance of CAF-tumor cell cross-talk and their influence on angiogenic and immune-components of TME are yet to be characterized in solid tumors, especially in endometrial cancers. Currently, the standard of care for the treatment of endometrial cancers is primarily guided by therapies directed towards the disease's tumor compartment and immune compartments. Unfortunately, in the current state of therapies, a complete response (CR) to the therapy is still limited despite a more commonly achieved partial response (PR) and stable disease (SD) in patients. Acknowledging the limitations of the current sets of therapies based on only the tumor and immune compartments of the disease, we sought to put forward this review based on the importance of the cross-talk between CAF of the tumor microenvironment and tumor cells. The premise of the review is to recognize the critical role of CAF in disease progression. This manuscript presents a systemic review of the role of CAF in endometrial cancers. We critically interrogated the active involvement of CAF in the tumor compartment of endometrial cancers. Here we present the functional characteristics of CAF in the context of endometrial cancers. We review (1) the characteristics of CAF, (2) their evolution from being anti-tumor to pro-tumor, (3) their involvement in regulating growth and several metastasis-associated phenotypes of tumor cells, (4) their participation in perturbing immune defense and evading immune surveillance, and (5) their role in mediating drug resistance via tumor-CAF cross-talk with particular reference to endometrial cancers. We interrogate the functional characteristics of CAF in the light of its dialogue with tumor cells and other components of TME towards developing a CAF-based strategy for precision therapy to supplement tumor-based therapy. The purpose of the review is to present a new vision and initiate a thought process which recognizes the importance of CAF in a tumor, thereby resulting in a novel approach to the design and management of the disease in endometrial cancers.

A subset of activated fibroblasts is associated with distant relapse in early luminal breast cancer.

BACKGROUND: Early luminal breast cancer (BC) represents 70% of newly diagnosed BC cases. Among them, small (under 2 cm) BC without lymph node metastasis (classified as T1N0) have been rarely studied, as their prognosis is generally favorable. Nevertheless, up to 5% of luminal T1N0 BC patients relapse with distant metastases that ultimately prove fatal. The aim of our work was to identify the mechanisms involved in metastatic recurrence in these patients. METHODS: Our study addresses the role that autonomous and non-autonomous tumor cell features play with regard to distant recurrence in early luminal BC patients. We created a cohort of T1N0 luminal BC patients (tumors between 0.5-2 cm without lymph node metastasis) with metastatic recurrence ("cases") and corresponding "controls" (without relapse) matched 1:1 on main prognostic factors: age, grade, and proliferation. We deciphered different characteristics of cancer cells and their tumor micro-environment (TME) by deep analyses using immunohistochemistry. We performed in vitro functional assays and highlighted a new mechanism of cooperation between cancer cells and one particular subset of cancer-associated fibroblasts (CAF). RESULTS: We found that specific TME features are indicative of relapse in early luminal BC. Indeed, quantitative histological analyses reveal that "cases" are characterized by significant accumulation of a particular CAF subset (CAF-S1) and decrease in CD4+ T lymphocytes, without any other association with immune cells. In multivariate analysis, TME features, in particular CAF-S1 enrichment, remain significantly associated with recurrence, thereby demonstrating their clinical relevance. Finally, by performing functional analyses, we demonstrated that CAF-S1 pro-metastatic activity is mediated by the CDH11/osteoblast cadherin, consistent with bones being a major site of metastases in luminal BC patients. CONCLUSIONS: This study shows that distant recurrence in T1N0 BC is strongly associated with the presence of CAF-S1 fibroblasts. Moreover, we identify CDH11 as a key player in CAF-S1-mediated pro-metastatic activity. This is independent of tumor cells and represents a new prognostic factor. These results could assist clinicians in identifying luminal BC patients with high risk of relapse. Targeted therapies against CAF-S1 using anti-FAP antibody or CDH11-targeting compounds might help in preventing relapse for such patients with activated stroma.

Lymphocyte activation gene 3 (LAG3) protein expression on tumor-infiltrating lymphocytes in aggressive and TP53-mutated salivary gland carcinomas.

Salivary gland carcinomas (SGCs) are rare and can be subdivided into distinct entities, some of which confer a poor prognosis. As targets for effective systemic therapy are warranted, some studies investigated the role of immune-checkpoint proteins PD-L1 and CTLA-4 in SGC. Our study depicts the expression of lymphocyte activation gene 3 (LAG3) in a test cohort and a larger validation cohort, totaling 139 SGCs. LAG3 is expressed on tumor-infiltrating lymphocytes (TILs), mediates T cell exhaustion and is subject to numerous currently recruiting clinical studies. Overall, one-third of SGCs were infiltrated by LAG3-expressing TILs with a strikingly high concordance between the test cohort and the validation cohort (30% and 28.2%, respectively). In the validation cohort, entity-wise LAG3 expression frequencies were highly variable. The highest rates were observed in salivary duct carcinoma (SDC; 66.7%) and adenocarcinoma not otherwise specified (ANOS; 50.0%). We observed LAG3 expression on effector T cells and in smaller frequencies also on FOXP3- T helper cells and FOXP3+ Tregs. LAG3 expression significantly correlated with advanced nodal metastases, cytotoxic T cell infiltrate and TP53 mutations. In the group of adenoid cystic carcinomas, LAG3 expression was also associated with a shorter event-free survival (EFS). Tumors with TP53 nonsense mutations (TP53 null type) exhibited higher LAG3 frequencies and a shorter EFS compared to TP53 wild type. This is the first report of LAG3 expression in SGC, a promising target for immunotherapy. LAG3 blockage could be distinctly applicable for SDC and ANOS, two SGC types with a particularly poor outcome.

TCR-engineered T cells to treat tumors: Seeing but not touching?

Adoptive transfer of T cells gene-engineered with T cell receptors (TCRs) has proven its feasibility and therapeutic potential in the treatment of malignant tumors. To ensure further clinical development of TCR gene therapy, it is necessary to accurately select TCRs that demonstrate antigen-selective responses that are restricted to tumor cells and, at the same time, include strategies that restore or enhance the entry, migration and local accumulation of T cells in tumor tissues. Here, we present the current standing of TCR-engineered T cell therapy, discuss and propose procedures to select TCRs as well as strategies to sensitize the tumor to T cell trafficking, and provide a rationale for combination therapies with TCR-engineered T cells.

Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review.

The treatment landscape in oncology has witnessed a major revolution with the introduction of checkpoint inhibitors: anti-PD1, anti-PDL1 and anti-CTLA-4. These agents enhance the immune response towards cancer cells instead of targeting the tumor itself, contrary to standard chemotherapy. Although long-lasting durable responses have been observed with immune checkpoints inhibitors, the response rate remains relatively low in many cases. Some patients respond in the beginning but then eventually develop acquired resistance to treatment and progress. Other patients having primary resistance never respond. Multiple studies have been conducted to further elucidate these variations in response in different tumor types and different individuals. This paper provides an overview of the mechanisms of resistance to immune checkpoint inhibitors and highlights the possible therapeutic approaches under investigation aiming to overcome such resistance in order to improve the clinical outcomes of cancer patients.

PD-L1 Expression and a High Tumor Infiltrate of CD8+ Lymphocytes Predict Outcome in Patients with Oropharyngeal Squamous Cells Carcinoma.

Carcinogenesis of human papillomavirus (HPV)-related (+) oropharyngeal squamous cell carcinoma (OPSCC) differs from HPV-negative (-) OPSCC. HPV-related immune-escape-mechanism could be responsible for the development and progression of HPV+ tumors and an immunophenotype different from HPV- OPSCC is expected. The purpose of this study was to analyze the expression of programmed cell death protein 1 ligand 1 (PD-L1) and its prognostic relevance in relation to CD8+ tumor infiltrating lymphocytes (TILs) and the major histocompatibility complex (MHC) I expression in OPSCC. We quantified PD-L1 expression on tumor cells (TC) and macrophages and MHC I expression in association to CD8+ TILs by immunohistochemistry on tissue microarray derived from 171 HPV+/-OPSCC. HPV-status was determined by p16INK4a immunohistochemistry/HPV-DNA detection. Presence of CD8+ TILs, PD-L1 expression on TC, and a more frequent loss of MHC I in HPV+ compared to HPV- OPSCC was detected. A high amount of CD8+ TILs in the whole cohort and in HPV+ OPSCC and PD-L1 expression on TC in HPV- OPSCC was associated with favorable overall survival. There was a trend for an improved outcome according to PD-L1 expression (macrophages) in HPV+ OPSCC without reaching statistical significance. CD8+ TILs and PD-L1-expression have prognostic impact in OPSCC and might present useful biomarkers for predicting clinical outcome and personalized therapy concepts.

A transatlantic perspective on the integration of immuno-oncology prognostic and predictive biomarkers in innovative clinical trial design.

Immuno-therapeutics aim to activate the body's own immune system against cancer and are one of the most promising cancer treatment strategies, but currently limited by a variable response rate. Biomarkers may help to distinguish those patients most likely to respond to therapy; they may also help guide clinical decision making for combination therapies, dosing schedules, and determining progression versus relapse. However, there is a need to confirm such biomarkers in preferably prospective clinical trials before they can be used in practice. Accordingly, it is essential that clinical trials for immuno-therapeutics incorporate biomarkers. Here, focusing on the specific setting of immune therapies, we discuss both the scientific and logistical hurdles to identifying potential biomarkers and testing them in clinical trials.