Immune checkpoint therapy-current perspectives and future directions.

Immune checkpoint therapy (ICT) has dramatically altered clinical outcomes for cancer patients and conferred durable clinical benefits, including cure in a subset of patients. Varying response rates across tumor types and the need for predictive biomarkers to optimize patient selection to maximize efficacy and minimize toxicities prompted efforts to unravel immune and non-immune factors regulating the responses to ICT. This review highlights the biology of anti-tumor immunity underlying response and resistance to ICT, discusses efforts to address the current challenges with ICT, and outlines strategies to guide the development of subsequent clinical trials and combinatorial efforts with ICT.

Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop.

Foxp3+ T regulatory (Treg) cells promote immunological tumor tolerance, but how their immune-suppressive function is regulated in the tumor microenvironment (TME) remains unknown. Here, we used intravital microscopy to characterize the cellular interactions that provide tumor-infiltrating Treg cells with critical activation signals. We found that the polyclonal Treg cell repertoire is pre-enriched to recognize antigens presented by tumor-associated conventional dendritic cells (cDCs). Unstable cDC contacts sufficed to sustain Treg cell function, whereas T helper cells were activated during stable interactions. Contact instability resulted from CTLA-4-dependent downregulation of co-stimulatory B7-family proteins on cDCs, mediated by Treg cells themselves. CTLA-4-blockade triggered CD28-dependent Treg cell hyper-proliferation in the TME, and concomitant Treg cell inactivation was required to achieve tumor rejection. Therefore, Treg cells self-regulate through a CTLA-4- and CD28-dependent feedback loop that adjusts their population size to the amount of local co-stimulation. Its disruption through CTLA-4-blockade may off-set therapeutic benefits in cancer patients.

B Cell Subsets and Immune Checkpoint Expression in Patients with Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by dysfunctional B cells. Immune checkpoint molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1 (PD-1) are upregulated in patients with CLL and may correlate with prognostic markers such as beta-2 microglobulin (B2M). The aim of this study was to evaluate the levels of immune checkpoints on B cell subsets and to further correlate them with B2M levels in patients with CLL. We recruited 21 patients with CLL and 12 controls. B cell subsets and the levels of immune checkpoint expression were determined using conventional multi-color flow cytometry. Basal levels of B2M in patients with CLL were measured using an enzyme-linked immunosorbent assay. Patients with CLL had increased levels of activated B cells when compared to the control group, p < 0.001. The expression of PD-1 and CTLA-4 were increased on activated B cells and memory B cells, p < 0.05. There were no associations between B2M levels and the measured immune checkpoints on B cell subsets, after adjusting for sex and age. In our cohort, the patients with CLL expressed elevated levels of PD-1 and CTLA-4 immune checkpoints on activated and memory B cell subsets. However, there was no correlation between these immune checkpoint expressions and B2M levels.

Preclinical models of cardiotoxicity from immune checkpoint inhibitor therapy.

Immune checkpoint inhibitor (ICI) therapy represents a ground-breaking paradigm in cancer treatment, harnessing the immune system to combat malignancies by targeting checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). The use of ICI therapy generates distinctive immune-related adverse events (irAEs) including cardiovascular toxicity, necessitating targeted research efforts. This comprehensive review explores preclinical models dedicated to ICI-mediated cardiovascular complications including myocarditis. Tailored preclinical models of ICI-mediated myocardial toxicities highlight the key role of CD8+ T cells, emphasizing the profound impact of immune checkpoints on maintaining cardiac integrity. Cytokines and macrophages were identified as possible driving factors in disease progression, and at the same time, initial data on possible cardiac antigens responsible are emerging. The implications of contributing factors including thoracic radiation, autoimmune disorder, and the presence of cancer itself are increasingly understood. Besides myocarditis, mouse models unveiled an accelerated progression of atherosclerosis, adding another layer for a thorough understanding of the diverse processes involving cardiovascular immune checkpoint signalling. This review aims to discuss current preclinical models of ICI cardiotoxicity and their potential for improving enhanced risk assessment and diagnostics, offering potential targets for innovative cardioprotective strategies. Lessons from ICI therapy can drive novel approaches in cardiovascular research, extending insights to areas such as myocardial infarction and heart failure.

Factors associated with liver injury and prognosis in advanced cancer patients treated with immune checkpoint inhibitors.

AIM: The use of immune checkpoint inhibitors (ICIs) has increased remarkably, and immune-related adverse events (irAEs) have also increased. This study aimed to identify factors associated with immune-related liver injury (irLI), and the relationship between the grades of irLI and overall survival (OS) in patients treated with ICIs. METHODS: A total of 571 patients who had been treated for advanced malignancies with ICIs between January 2015 and March 2022 were retrospectively recruited. The presence of liver injury was determined by the aspartate aminotransferase and alanine aminotransferase elevation. The irLI grading was based on Common Terminology Criteria for Adverse Events version 5.0. RESULTS: A total of 50 (8.8%) patients had grade ≥2 irLI and 24 (4.2%) had grade ≥3 irLI. Treatment with anti-cytotoxic T-lymphocyte-associated protein-4 agents and baseline grade 1 aspartate aminotransferase/alanine aminotransferase elevation were independent predictive factors of grade ≥2 irLI. Treatment with anti-cytotoxic T-lymphocyte-associated protein-4 was the only independent predictive factor of grade ≥3 irLI. The median OS for patients who experienced any irAEs was significantly longer than of those without irAEs (hazard ratio 0.503, 95% CI 0.398-0.636, p < 0.001). The median OS in patients with grade ≥2 irLI was significantly longer (HR 0.570, 95% CI 0.387-0.838, p = 0.022). There was no significant difference between the median OS in patients with grade ≥3 irLI and the others (p = 0.11). CONCLUSION: The incidence of irLI was significantly higher in patients treated with anti-cytotoxic T-lymphocyte-associated protein-4 agents. Even in patients with pre-existing grade 1 aspartate aminotransferase/alanine aminotransferase elevation, appropriate follow-up and control of the irLI can improve the prognosis.

Immune checkpoint inhibitor-associated acute kidney injury in patients with cancer: a systematic review and meta-analysis of risk factors.

BACKGROUND: As a novel antineoplastic drug, immune checkpoint inhibitors (ICIs) are associated with a spectrum of autoimmune-related side effects, including acute kidney injury (AKI). Understanding the risk factors for immune-associated acute kidney injury will inform future symptom management measures to reduce this risk. This study aims to identify the risk factors for ICIs-AKI in cancer patients through a systematic review and meta-analysis. METHODS: The systematic search was conducted in The Cochrane Library, Pubmed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Data, and VIP Database. The related studies published since the establishment of the database to Aug 22, 2022, were screened, data was extracted following the inclusion and exclusion criteria, and the quality of the selected studies was assessed by Newcastle-Ottawa Scale (NOS). The above was performed independently by the two reviewers. The estimated pooled odds ratios (ORs) for risk factors of developing ICIs-AKI were conducted by random-effects meta-analysis. RESULTS: A total of 8 publications, including 5267 patients, were included. Meta-analysis results showed that extrarenal immune-related adverse events (irAEs), therapy with the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), male, hypertension, pre-existent use of a diuretic, and a proton pump inhibitor (PPI) were significantly correlated to ICIs-AKI. CONCLUSIONS: We identified extrarenal irAEs, CTLA-4 treatments, males, hypertension, previous use of diuretics, and PPIs are essential predictors of ICIs-AKI. These findings are helpful for healthcare providers to monitor ICIs-AKI for management and timely interventions.

Tolerated Re-Challenge of Immunotherapy in a Patient with ICI Associated Myocarditis: A Case Report and Literature Review.

Many different types of cancer can be treated with immunotherapy drugs called immune checkpoint inhibitors (ICIs). These drugs have altered the landscape of cancer treatment options since they function by triggering a stronger immune response to malignancy. As expected, ICIs' modification of immune regulatory controls leads to a wide range of organ/gland-specific immune-related side effects. These adverse effects are uncommonly deadly and typically improve by discontinuing treatment or administering corticosteroid drugs. As a result of a number of factors-including a lack of specificity in the clinical presentation, the possibility of overlap with other cardiovascular and general medical illnesses, difficulties in diagnosis, and a general lack of awareness-the true incidence of ICI-associated myocarditis is likely underestimated. Currently, protocols for the surveillance, diagnosis, or treatment of this condition are unclear. Several questions remain unanswered, such as how to best screen for this rare toxin, what tests should be run on patients who are suspected of having it, how to treat myocarditis once it has developed, and who is at most risk. In this article, we provide a case study of ICI-associated myocarditis and explain its key characteristics and treatment options.

Comparison of the Effectiveness of IgG Antibody versus F(ab')2 Antibody Fragment in CTLA4-Targeted Near-Infrared Photoimmunotherapy.

Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment modality that utilizes antibody-photoabsorber conjugates (APCs) and selectively kills target cells after irradiation with NIR light. Originally, NIR-PIT was targeted against cancer cell surface antigens, but as it became clear that NIR-PIT induced a strong immune response, an effort was made to target selected immune cell populations in the tumor microenvironment to encourage an even stronger immune response. Thus, CD25-targeted NIR-PIT and cytotoxic T-lymphocyte associated protein 4 (CTLA4)-targeted NIR-PIT were developed to kill regulatory T cells (Tregs) in conjunction with cancer-cell-targeted NIR-PIT, in order to amplify the host immune response. It was found that CD25-targeted NIR-PIT, using an antibody with the Fc portion removed, led to better results than the unmodified anti-CD25 antibody-directed NIR-PIT presumably because of a negative effect on activated T cells. The aim of this study was to compare the efficacy of an antibody fragment [anti-CTLA4-F(ab')2] and a whole antibody (anti-CTLA4-IgG) for NIR-PIT. There was no significant difference in NIR-PIT-induced Treg killing between the anti-CTLA4-F(ab')2 and anti-CTLA4-IgG antibodies. Although both the antibody and the antibody fragment resulted in significant tumor growth inhibition, the antibody induced more robust CD8+ T cell activation in ipsilateral lymph nodes and was more effective compared to the antibody fragment. The slower clearance of the anti-CTLA4-IgG APC enhanced antitumor immunity by promoting T cell priming in lymph nodes. In conclusion, unlike the results with CD25 where modified antibodies produced superior results to unmodified antibodies, anti-CTLA4-IgG antibody-based NIR-PIT proved more effective in reducing tumor growth than anti-CTLA4-F(ab')2 antibody-based NIR-PIT.

Malignant mesothelioma: Advances in immune checkpoint inhibitor and mesothelin-targeted therapies.

Malignant mesothelioma is an aggressive cancer with a poor prognosis and limited treatment options. For many years, the only US Food and Drug Administration-approved first-line treatment for unresectable mesothelioma was pemetrexed plus cisplatin. However, the recent approval of nivolumab plus ipilimumab as frontline treatment for patients with pleural mesothelioma marks a significant milestone for the treatment of this disease. In this review, the authors describe recent advances in therapeutic strategies for the treatment of patients with advanced, unresectable mesothelioma, highlighting the emerging use of immunotherapy and mesothelin-targeted therapies for the management of malignant mesothelioma.

Cytotoxic T-lymphocyte-associated protein 4 in gastric cancer: Prognosis and association with PD-L1 expression.

BACKGROUND: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is one of the most studied immune checkpoint in gastric cancer (GC). However, the prognostic role of CTLA-4 expression in GC is poorly described. This study aimed to evaluate CTLA-4 expression in GC and its impact on survival, including patients treated with standard platinum-based chemotherapy (CMT), and association with PD-L1 expression. METHODS: All GC patients who underwent D2-gastrectomy were investigated retrospectively. Tumor samples were examined for CTLA-4 and PD-L1 by immunohistochemistry. Tumor-infiltrating inflammatory cells, including CD4 + and CD8 + , were also examined. RESULTS: Among the 284 GC patients included, 159 (56%) were CTLA-4 positive and the remaining 125 (44%) were classified as negative. CTLA-4 positive GC was associated with increased inflammatory cell infiltration (p < 0.001), high CD8 + T cells (p = 0.016) and PD-L1 expression (p = 0.026). Considering GC referred for treatment, CTLA-4 negative patients who received CMT had a significant improvement in disease-free survival compared to untreated CLTA-4 negative (p = 0.028). In multivariate analysis, GC positive for both CTLA-4 and PD-L1 had a prognostic impact on survival. CONCLUSION: CTLA-4 positive was associated with PD-L1 expression and a high tumor-infiltrating CD8 + T cells. Accordingly, positivity for both CTLA-4 and PD-L1 was an independent factor associated to better survival in GC patients.

Tumor-Infiltrating T Cells Concurrently Overexpress CD200R with Immune Checkpoints PD-1, CTLA-4, and TIM-3 in Non-Small-Cell Lung Cancer.

INTRODUCTION: CD200R has been reported to be the receptor for the immune checkpoint molecule CD200 and can transduce immune-suppressive signals. In this study, we mainly focused on the expression level of CD200R in T cells in pulmonary artery (PA) blood and non-small-cell lung cancer (NSCLC) tumor tissue. METHODS: Immune cells were isolated from dissected tumor samples and PA blood of NSCLC patients and analyzed with multiparameter flow cytometry. The co-expression of CD200R with other immune checkpoints, including programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), was also investigated. RESULTS: CD200R expression was observed on the surface of approximately 75% of T cells among tumor-infiltrating leukocytes (TILs). Compared to T cells extracted from TILs, only 55% of T cells extracted from PA blood exhibited CD200R expression. Moreover, with higher expression of CD200R, the expression of other immune checkpoints, including PD-1, CTLA-4, and TIM-3, was also increased in tumor-infiltrating T cells compared to T cells in PA blood. CONCLUSIONS: Our results showed that those tumors were dominated by T cells expressing CD200R together with other checkpoints, which suggests a phenotypic change after T cell infiltration into the tumor, such as T cell exhaustion.

Magnifying endoscopy with crystal violet staining for immune checkpoint inhibitor-associated colitis.

BACKGROUND AND AIM: There exists no evidence on the relationship between endoscopic and histologic findings. Furthermore, even after multiple biopsy specimens were obtained, histologic examination usually fails to show the characteristic features of immune checkpoint inhibitor-associated colitis. In this study, we explored the endoscopic and histologic findings of immune checkpoint inhibitor-associated colitis. METHODS: Patients diagnosed with immune checkpoint inhibitor-associated colitis at our hospital between March 2018 and December 2018 were retrospectively assessed. The degree of mucosal inflammation was evaluated using endoscopic inflammation grade (inactive, mild, moderate, or severe disease) and further observed using magnifying endoscopy with crystal violet staining. Pit structures were classified into three types: regularly arranged pits with circular or elliptical shape (R type), irregularly arranged pits with inhomogeneous size and morphology (IR type), and pits with reduced density or pits that partially disappeared (AD type). RESULTS: Eleven patients (median age, 71 years; range, 44-83 years) were diagnosed with immune checkpoint inhibitor-associated colitis. All characteristic histologic findings, including crypt distortion, crypt abscesses, and apoptotic bodies, were observed at sites with moderate-to-severe endoscopic inflammation but not at sites with inactive-to-mild endoscopic inflammation. Characteristic histologic features were observed in 0%, 50%, and 100% of R-type, IR-type, and AD-type mucosa, respectively. CONCLUSIONS: We revealed the possible utility of endoscopic images for selecting suitable target sites for biopsy and showed that endoscopic findings could reduce the time lag associated with tissue diagnosis and sampling errors due to biopsy.

Modest efficacy of nivolumab plus ipilimumab in patients with papillary renal cell carcinoma.

PURPOSE: Combined immunotherapy of nivolumab plus ipilimumab for intermediate- and poor-risk metastatic clear cell renal cell carcinoma showed prolonged progression-free survival and high objective response rate in a randomized phase III clinical trial. However, the efficacy of this treatment for papillary renal cell carcinoma remains unclear. In the present study, we analysed the efficacy of nivolumab plus ipilimumab therapy for papillary renal cell carcinoma compared with that for clear cell renal cell carcinoma. MATERIALS AND METHODS: This is a retrospective study of 30 patients with metastatic renal cell carcinoma who received nivolumab and ipilimumab as first-line therapy between December 2015 and May 2020. The objective response rate, progression-free survival and toxicity were compared between the two groups (clear cell renal cell carcinoma and papillary renal cell carcinoma). RESULTS: Out of 30 patients, 7 and 23 were diagnosed with papillary renal cell carcinoma and clear cell renal cell carcinoma, respectively. With a median follow-up of 7.2 months, the median progression-free survival was significantly shorter in papillary renal cell carcinoma than in clear cell renal cell carcinoma (2.4 vs. 28.1 months, P = 0.014). Of the seven patients with papillary renal cell carcinoma, one had partial response, one had stable disease and five had progressive disease, resulting in an objective response rate of 14.2%, which was lower compared to that of clear cell renal cell carcinoma (14.2 vs. 52.1%, P = 0.06). Discontinuation due to toxicity was not observed with papillary renal cell carcinoma, meanwhile 60.8% of patient with clear cell renal cell carcinoma discontinued treatment due to toxicity. CONCLUSION: Nivolumab plus ipilimumab had modest efficacy for papillary renal cell carcinoma compared with that for clear cell renal cell carcinoma. Nivolumab plus ipilimumab remains an option for a limited number of patients with intermediate- or poor-risk papillary renal cell carcinoma.

Response rate and local recurrence after concurrent immune checkpoint therapy and radiotherapy for non-small cell lung cancer and melanoma brain metastases.

BACKGROUND: Prior literature has suggested synergy between immune checkpoint therapy (ICT) and radiotherapy (RT) for the treatment of brain metastases (BrM), but to the authors' knowledge the optimal timing of therapy to maximize this synergy is unclear. METHODS: A total of 199 patients with melanoma and non-small cell lung cancer with BrM received ICT and RT between 2007 and 2016 at the study institution. To reduce selection biases, individual metastases were included only if they were treated with RT within 90 days of ICT. Concurrent treatment was defined as RT delivered on the same day as or in between doses of an ICT course; all other treatment was considered to be nonconcurrent. Multivariable Cox proportional hazards models were used to assess time to response and local disease recurrence on a per-metastasis basis, using a sandwich estimator to account for intrapatient correlation. RESULTS: The final cohort included 110 patients with 340 BrM, with 102 BrM treated concurrently and 238 BrM treated nonconcurrently. Response rates were higher with the use of concurrent treatment (70% vs 47%; P < .001), with correspondingly lower rates of progressive disease (5% vs 26%; P < .001). On multivariable analysis, concurrent treatment was found to be associated with improved time to response (hazard ratio, 1.76; 95% CI, 1.18-2.63 [P = .006]) and decreased local recurrence (hazard ratio, 0.42; 95% CI, 0.23-0.78 [P = .006]). This effect appeared to be greater for melanoma than for non-small cell lung cancer, although interaction tests were not statistically significant. Only 1 of 103 metastases which had a complete response later developed disease progression. CONCLUSIONS: Concurrent RT and ICT may improve response rates and decrease local recurrence of brain metastases compared with treatment that was nonconcurrent but delivered within 90 days. Further study of this combination in prospective, randomized trials is warranted.

Immune checkpoint blockade in solid organ tumours: Choice, dose and predictors of response.

Immune checkpoint blockade has transformed outcomes across solid organ tumours. Monoclonal antibodies targeting the negative inhibitory cytotoxic T lymphocyte-associated protein 4 and programmed-death 1/programmed death-ligand 1 axis can lead to deep and durable responses across several tumour streams in the advanced setting. This immunotherapy approach is increasingly used earlier in the treatment paradigm. A rapidly evolving regulatory, reimbursement and drug development landscape has accompanied this novel class of immunotherapy. Unfortunately, only a small proportion of patients respond meaningfully to these agents. Here we review how the underlying tumoural genomic, histological and immunological characteristics interact within various patient phenotypes, leading to variations in response to checkpoint blockade. Concurrently, we outline the clinical trial and real-world evidence that allows for appropriate selection of agent, dose and schedule in solid organ malignancies. An exploration of current trends in basic and translational research in immune checkpoint blockade accompanies a commentary on future clinical directions for checkpoint blockade in oncology.

Cancer immunotherapy-related adverse events: causes and challenges.

Despite the success and ongoing promise of monoclonal antibody-targeted immune checkpoint inhibitor immunotherapy of advanced malignancies, in particular, antibodies directed against CTLA-4 and PD-1/PD-L1, the development of immune-related adverse events (irAEs) remains a constraint of this type of therapy. Although rarely fatal, the occurrence of irAEs may necessitate discontinuation of immunotherapy, as well as administration of corticosteroids or other immunosuppressive therapies that may not only compromise efficacy but also predispose for development of opportunistic infection. Clearly, retention of efficacy of immune checkpoint-targeted therapies with concurrent attenuation of immune-mediated toxicity represents a formidable challenge. In this context, the current brief review examines mechanistic relationships between these events, as well as recent insights into immunopathogenesis, and strategies which may contribute to resolving this issue. These sections are preceded by brief overviews of the discovery and functions of CTLA-4 and PD-1, as well as the chronology of the development of immunotherapeutic monoclonal antibodies which target these immune checkpoint inhibitors.

Association of cytotoxic T-lymphocyte associated protein 4 gene polymorphisms with the risk and prognosis of oesophageal cancer in a high-incidence region from northern China.

The most important anti-tumour immune response is mediated by T lymphocytes. Cytotoxic T lymphocyte-associated protein 4 (CTLA4) plays a critical role in the immune surveillance against tumours as an inhibitory immune checkpoint molecule of T-cell activation. This study was designed to explore the association of CTLA4 polymorphisms with the susceptibility to oesophageal squamous cell carcinoma (ESCC) and prognosis of patients with ESCC in a high-incidence population from northern China. CTLA4 rs5742909 C/T and rs231775 G/A single nucleotide polymorphisms (SNPs) were genotyped using polymerase chain reaction-ligase detection reaction (PCR-LDR) method in 577 ESCC patients and 580 controls. Upper gastrointestinal cancer family history increased the risk of ESCC (the sex-, age- and smoking status-adjusted OR = 1.383, 95%CI = 1.094-1.749). The genotype frequencies of these two SNPs in the patients with ESCC were similar to that in the controls. Survival analyses were conducted in 204 patients with ESCC with five-year survival information. The mean survival time of ESCC patients with rs231775 SNP A/A genotype in age over 60 years group was 23.2 months, significantly shorter than that of those with G/G genotype (47.3 months). The A/A genotype was associated with increased death risk of patients with ESCC older than 60 years (adjusted HR = 4.544, 95%CI = 1.913-10.790). CTLA4 rs231775 SNP might be used as genetic marker of worse prognosis for patients with ESCC over 60 years in a high-incidence population from northern China.

Anti-pituitary antibodies as a marker of autoimmunity in pituitary glands.

Autoimmunity contributes to the pathogenesis of hypophysitis, a chronic inflammatory disease in the pituitary gland. Although primary hypophysitis is rare, the number of pituitary dysfunction cases induced by immune checkpoint inhibitors (ICIs) is increasing. While it is difficult to prove the involvement of autoimmunity in the pituitary glands, circulating anti-pituitary antibodies (APAs) can be measured by indirect immunofluorescence and used as a surrogate marker of pituitary autoimmunity. APAs are present in several pituitary diseases, including lymphocytic adenohypophysitis, lymphocytic infundibulo-neurohypophysitis (LINH), IgG4-related hypophysitis, and pituitary dysfunction induced by ICIs. Mass spectrometry analysis of antigens targeted by APAs clarified rabphilin-3A as an autoantigen in LINH. This demonstrates that APAs can be applied as a probe to identify novel autoantigens in other pituitary autoimmune diseases, including pituitary dysfunction induced by ICIs, which can aid in biomarker discovery.

Tumor Microenvironment in Penile Cancer.

Penile cancer is rare but associated with a high morbidity and mortality once metastasized. Besides presenting a fundamental overview of penile cancer, the current literature on key players associated with the pathogenesis of penile cancer including common labor chemistry parameters [neutrophil to lymphocyte ratio (NLR) and C-reactive protein CrP)], programmed cell death 1 (PD1)/PD ligand 1 (PD-L1), regulatory T cells (Tregs), forkhead box protein 3 (FoxP3, also known as scurfin), Ki-67 (also known as MKI67), protein 53 (p53), and pericytes has been reviewed and summarized. Furthermore, future directions and an overview of ongoing clinical trials are provided to highlight potential avenues that could improve cancer-specific and overall survival.

The Impact of Estrogen in the Tumor Microenvironment.

Tumor immune escape is now a hallmark of cancer development, and therapies targeting these pathways have emerged as standard of care. Specifically, immune checkpoint signal blockade offers durable responses and increased overall survival. However, the majority of cancer patients still do not respond to checkpoint blockade immune therapy leading to an unmet need in tumor immunology research. Sex-based differences have been noted in the use of cancer immunotherapy suggesting that sex hormones such as estrogen may play an important role in tumor immune regulation. Estrogen signaling already has a known role in autoimmunity, and the estrogen receptor can be expressed across multiple immune cell populations and effect their regulation. While it has been well established that tumor cells such as ovarian carcinoma, breast carcinoma, and even lung carcinoma can be regulated by estrogen, research into the role of estrogen in the regulation of tumor-associated immune cells is still emerging. In this chapter, we discuss the role of estrogen in the tumor immune microenvironment and the possible immunotherapeutic implications of targeting estrogen in cancer patients.