SIRPG expression positively associates with an inflamed tumor microenvironment and response to PD-1 blockade.

BACKGROUND: This study aimed to investigate the relationship between signal regulatory protein gamma (SIRPG) and tumor immune microenvironment phenotypes or T cell mediated-adaptive antitumor immunity, and its predictive value for response to PD-1 blockade in cancers. METHODS: Pan-cancer analysis of SIRPG expression and immune deconvolution was performed using transcriptomic data across 33 tumor types. Transcriptomic and clinical data from 157 patients with non-small-cell lung cancer (NSCLC) and melanoma received PD-1 blockade were analyzed. Expression characteristics of SIRPG were investigated using single-cell RNA sequencing (scRNA-seq) data of 103,599 cells. The effect of SIRPG expression was evaluated via SIRPG knockdown or overexpression in Jurkat T cells. RESULTS: The results showed that most cancers with high SIRPG expression had significantly higher abundance of T cells, B cells, NK cells, M1 macrophages and cytotoxic lymphocytes and increased expression level of immunomodulatory factors regulating immune cell recruitment, antigen presentation, T cell activation and cytotoxicity, but markedly lower abundance of neutrophils, M2 macrophages, and myeloid-derived suppressor cells. High SIRPG expression was associated with favorable response to PD-1 blockade in both NSCLC and melanoma. scRNA-seq data suggested SIRPG was mainly expressed in CD8+ exhausted T and CD4+ regulatory T cells, and positively associated with immune checkpoint expression including PDCD1 and CTLA4. In vitro test showed SIRPG expression in T cells could facilitate expression of PDCD1 and CTLA4. CONCLUSION: High SIRPG expression is associated with an inflamed immune phenotype in cancers and favorable response to PD-1 blockade, suggesting it would be a promising predictive biomarker for PD-1 blockade and novel immunotherapeutic target.

Camrelizumab plus famitinib in previously chemo-immunotherapy treated patients with advanced NSCLC: results from an open-label multicenter phase 2 basket study.

BACKGROUND: The combination of immune checkpoint inhibitors and antiangiogenic agents has been effective in treating multiple cancers. This was further explored in an open-label, multicenter phase 2 basket study (NCT04346381), which evaluated the antitumor activity and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (a receptor tyrosine kinase inhibitor) in patients with advanced solid tumors. We herein report the findings from the cohort of advanced NSCLC patients who progressed after treatment with platinum-doublet chemotherapy and immunotherapy. METHODS: Eligible patients were enrolled and treated with camrelizumab (200 mg once every 3 weeks via intravenous infusion) and oral famitinib (20 mg once daily). The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty patients were enrolled in this cohort, with a median follow-up duration of 11.5 months. Three patients (7.5%) achieved a partial response, and 29 patients (72.5%) achieved stable disease. The ORR and DCR with this combination regimen were 7.5% (95% CI, 1.6-20.4) and 80.0% (95% CI, 64.4-90.9), respectively. The median DoR was 12.1 months (95% CI, 10.3-not reached). The median PFS was 5.4 months (95% CI, 4.1-7.5), and the median OS was 12.1 months (95% CI, 9.1-16.7). The estimated 12-month OS rate was 51.5% (95% CI, 34.9-65.9). The most frequent grade 3 or higher treatment-related adverse events occurring in more than 5% of patients included hypertension (27.5%), palmar-plantar erythrodysesthesia syndrome (10%), decreased neutrophil count (10%), and proteinuria (7.5%). CONCLUSION: Camrelizumab plus famitinib demonstrated favorable benefits in PFS and OS, along with manageable safety profiles, in patients with advanced NSCLC who progressed after platinum-doublet chemotherapy and immunotherapy. This finding warrants further exploration.

GPNMB Expression Associates with Inferior Prognosis in Patients with Small Cell Lung Cancer.

Purpose: Small cell lung cancer (SCLC) is widely recognized for its propensity for early and frequent metastases, which contribute to its status as a refractory malignancy. While the high expression of GPNMB in SCLC is well-documented, the precise correlation between GPNMB expression and the prognosis of SCLC remains undetermined. Methods: HTG Edge-seq was used to screen the differential gene expression between primary SCLC lesions and paired metastatic lymph nodes (LN). The plasma concentration of GPNMB was measured using enzyme-linked immunosorbent assay (ELISA). The relationship between GPNMB concentration and clinical characteristics, as well as overall survival (OS) was assessed. One-to-one propensity score matching (PSM) was performed to reduce bias from confounding factors between groups. The invasive, migratory, proliferative, and apoptotic abilities of SCLC cells were evaluated using migration and matrigel invasion assays, CCK8 assay and flow cytometry respectively. Results: GPNMB exhibited a significant up-regulation in LN compared to primary SCLC lesions as determined by HTG Edge-seq. Furthermore, patients with extensive disease demonstrated a significantly elevated plasma GPNMB concentration compared to those with local disease (P = 0.043). Additionally, patients with a high baseline plasma GPNMB level exhibited a shorter OS (10.32 vs. 16.10 months, P = 0.0299). Following PSM analysis, the statistical significance of the difference between the two groups persisted (9.43 vs. 15.27 months, P = 0.0146). Notably, both univariate and multivariate analyses confirmed that higher expression of GPNMB served as an independent biomarker for OS before PSM (P = 0.033, HR = 2.304) and after PSM (P = 0.003, HR = 6.190). Additionally, our study revealed that the inhibition of GPNMB expression through the use of siRNA effectively diminished the metastatic and proliferative capabilities of SCLC. Furthermore, this inhibition resulted in an enhanced ability to induce apoptosis. Conclusions: In light of our findings, it can be inferred that the expression of GPNMB is linked to metastasis and an unfavorable prognosis, thus suggesting its potential as a novel therapeutic target in the treatment of SCLC.

Induction immunochemotherapy followed by definitive chemoradiotherapy for unresectable locally advanced non-small cell lung cancer: a multi-institutional retrospective cohort study.

This study aimed to evaluate the efficacy and safety of induction immunochemotherapy followed by definitive chemoradiotherapy (CRT) for unresectable locally advanced non-small cell lung cancer (LA-NSCLC). We identified unresectable stage III NSCLC patients who received induction immunochemotherapy. Overall survival (OS) and progression-free survival (PFS) were the primary endpoints. From February 2019 to August 2022, 158 patients were enrolled. Following the completion of induction immunochemotherapy, the objective response rate (ORR) and disease control rate (DCR) were 52.5% and 83.5%, respectively. The ORR of CRT was 73.5%, representing 68.4% of the total cohort. The median PFS was 17.8 months, and the median OS was 41.9 months, significantly higher than in patients who received CRT alone (p < 0.001). Patients with concurrent CRT demonstrated markedly improved PFS (p = 0.012) and OS (p = 0.017) than those undergoing sequential CRT. Additionally, those with a programmed-death ligand 1 (PD-L1) expression of 50% or higher showed significantly elevated ORRs (72.2% vs. 47.2%, p = 0.011) and superior OS (median 44.8 vs. 28.6 months, p = 0.004) compared to patients with PD-L1 expression below 50%. Hematologic toxicities were the primary severe adverse events (grade ≥ 3) encountered, with no unforeseen treatment-related toxicities. Thus, induction immunochemotherapy followed by definitive CRT demonstrated encouraging efficacy and tolerable toxicities for unresectable LA-NSCLC.

Targeting focal adhesion kinase boosts immune response in KRAS/LKB1 co-mutated lung adenocarcinoma via remodeling the tumor microenvironment.

BACKGROUND: KRAS mutation is one of the most common oncogenic drivers in NSCLC, however, the response to immunotherapy is heterogeneous owing to the distinct co-occurring genomic alterations. KRAS/LKB1 co-mutated lung adenocarcinoma displays poor response to PD-1 blockade whereas the mechanism remains undetermined. METHODS: We explored the specific characteristics of tumor microenvironment (TME) in KL tumors using syngeneic KRASG12DLKB1-/- (KL) and KRASG12DTP53-/- (KP) lung cancer mouse models. The impact of focal adhesion kinase (FAK) inhibitor on KL lung tumors was investigated in vitro and in vivo through evaluation of both KL cell lines and KL lung cancer mouse models. RESULTS: We identified KL tumors as "immune-cold" tumors with excessive extracellular matrix (ECM) collagen deposition that formed a physical barrier to block the infiltration of CD8+T cells. Mechanistically, abundant activated cancer-associated fibroblasts (CAFs) resulted from FAK activation contributed to the formation of the unique TME of KL tumors. FAK inhibition with a small molecular inhibitor could remodel the TME by inhibiting CAFs activation, decreasing collagen deposition and further facilitating the infiltration of anti-tumor immune cells, including CD8+ T cells, DC cells and M1-like macrophages into tumors, hence, converting "immune-cold" KL tumors into "immune-hot" tumors. The combined FAK inhibitor and PD-1 blockade therapy synergistically retarded primary and metastatic tumor growth of KL tumors. CONCLUSIONS: Our study identified FAK as a promising intervention target for KL tumors and provided basis for the combination of FAK inhibitor with PD-1 blockade in the management of KL lung cancers.

Efficacy and safety of local ablative therapy for patients with NSCLC and coexisting interstitial lung disease.

BACKGROUND: The effective therapeutic approach is still an unmet need for patients diagnosed with both lung cancer and interstitial lung disease (ILD). This is primarily due to the possible risk of ILD exacerbation caused by surgery or radiotherapy. The current study aimed to investigate the efficacy and safety of local ablative therapy (LAT) for this specific population. METHODS: Consecutive patients with non-small cell lung cancer (NSCLC) and ILD who received LAT between January 2018 and August 2022 were enrolled, and propensity score matching (PSM) was utilized to match the non-ILD group. The primary endpoint was recurrence-free survival (RFS), and secondary endpoints included overall survival (OS), adverse events (AEs) and hospital length of stay (HLOS). RESULTS: The PSM algorithm yielded matched pairs in the ILD group (n = 25) and non-ILD group (n = 72) at a ratio of 1:3. There were no statistically significant differences in RFS (median 16.4 vs. 18 months; HR = 1.452, p = 0.259) and OS (median: not reached vs. 47.9 months; HR = 1.096, p = 0.884) between the two groups. Meanwhile, no acute exacerbation of ILD was observed in the ILD group. However, the incidence of pneumothorax, especially pneumothorax requiring chest tube drainage, was significantly higher (36.0% vs. 11.2%, p = 0.005) among patients with NSCLC and co-existing ILD, which resulted in longer HLOS (p = 0.045). CONCLUSION: Although ILD was associated with a higher incidence of pneumothorax, the efficacy of LAT for NSCLC patients with ILD was comparable to those without ILD, suggesting that LAT might be a reliable and effective treatment option for this population, particularly in the early stage.

Genomic correlates of the response to first-line PD-1 blockade plus chemotherapy in patients with advanced non-small-cell lung cancer.

BACKGROUND: Programmed death 1 (PD-1) blockade plus chemotherapy has become the new first-line standard of care for patients with advanced non-small-cell lung cancer (NSCLC). Yet not all NSCLC patients benefit from this regimen. This study aimed to investigate the predictors of PD-1 blockade plus chemotherapy in untreated advanced NSCLC. METHODS: We integrated clinical, genomic, and survival data from 287 patients with untreated advanced NSCLC who were enrolled in one of five registered phase 3 trials and received PD-1 blockade plus chemotherapy or chemotherapy alone. We randomly assigned these patients into a discovery cohort (n = 125), a validation cohort (n = 82), and a control cohort (n = 80). The candidate genes that could predict the response to PD-1 blockade plus chemotherapy were identified using data from the discovery cohort and their predictive values were then evaluated in the three cohorts. Immune deconvolution was conducted using transcriptome data of 1014 NSCLC patients from The Cancer Genome Atlas dataset. RESULTS: A genomic variation signature, in which one or more of the 15 candidate genes were altered, was correlated with significantly inferior response rates and survival outcomes in patients treated with first-line PD-1 blockade plus chemotherapy in both discovery and validation cohorts. Its predictive value held in multivariate analyses when adjusted for baseline parameters, programmed cell death ligand 1 (PD-L1) expression level, and tumor mutation burden. Moreover, applying both the 15-gene panel and PD-L1 expression level produced better performance than either alone in predicting benefit from this treatment combination. Immune landscape analyses revealed that tumors with one or more variation in the 15-gene panel were associated with few immune infiltrates, indicating an immune-desert tumor microenvironment. CONCLUSION: These findings indicate that a 15-gene panel can serve as a negative prediction biomarker for first-line PD-1 blockade plus chemotherapy in patients with advanced NSCLC.

First-line treatment with camrelizumab plus famitinib in advanced or metastatic NSCLC patients with PD-L1 TPS ≥1%: results from a multicenter, open-label, phase 2 trial.

BACKGROUND: The combination of immune-checkpoint inhibitors and antiangiogenic agents can synergistically modulate the tumor microenvironment and represents a promising treatment option. Here, we evaluated the efficacy and safety of camrelizumab plus famitinib (a receptor tyrosine kinase inhibitor) as a first-line treatment for advanced or metastatic NSCLC patients with a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥1%, in an open-label, multicenter, phase 2 basket trial. METHODS: Eligible patients received camrelizumab (200 mg once every 3 weeks via intravenous infusion) plus oral famitinib at an initial dose of 20 mg once daily. The primary endpoint was the objective response rate (ORR), as assessed by the investigator per Response Evaluation Criteria in Solid Tumors V.1.1. Key secondary endpoints included disease control rate (DCR), duration of respons, progression-free survival (PFS), overall survival (OS), 12-month OS rate, and safety profile. RESULTS: Of the enrolled 41 patients, 21 (51.2%) had a PD-L1 TPS of 1-49%. As of the cut-off date on June 22, 2022, the combination regimen of camrelizumab and famitinib achieved an ORR of 53.7% (95% CI 37.4% to 69.3%) and a DCR of 92.7% (95% CI 80.1% to 98.5%). The median PFS was 16.6 months (95% CI 8.3 to not reached), and OS data were not yet mature, with an estimated 12-month OS rate of 76.8% (95% CI 60.0% to 87.3%). The most common treatment-related adverse events of grade 3 or higher included hypertension (22.0%), increased alanine aminotransferase (12.2%), decreased neutrophil count (9.8%), proteinuria (7.3%), decrease platelet count (7.3%), and hypokalemia (7.3%). One (2.4%) patient died from grade 5 hemoptysis, which was considered possibly related to the study treatment by the investigator. CONCLUSION: Camrelizumab plus famitinib demonstrated promising antitumor activity in advanced or metastatic NSCLC patients and had an acceptable safety profile. These findings suggest that this combination regimen could be an alternative therapeutic option and warrant further investigation. TRIAL REGISTRATION NUMBER: NCT04346381.

Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer.

KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrated robust efficacy against KRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibited promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR-Cas9 screening, which unveiled proteasome as a sensitization target. We further observed that the proteasome inhibitor, carfilzomib, improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, either as a single agent or in combination with carfilzomib, reshaped the tumor microenvironment toward an immune-permissive one. In summary, this study provides potential therapies for patients with KRAS G12D-mutant cancers, for whom effective treatments are currently lacking.

EML4-ALK fusions drive lung adeno-to-squamous transition through JAK-STAT activation.

Human lung adenosquamous cell carcinoma (LUAS), containing both adenomatous and squamous pathologies, exhibits strong cancer plasticity. We find that ALK rearrangement is detectable in 5.1-7.5% of human LUAS, and transgenic expression of EML4-ALK drives lung adenocarcinoma (LUAD) formation initially and squamous transition at late stage. We identify club cells as the main cell-of-origin for squamous transition. Through recapitulating lineage transition in organoid system, we identify JAK-STAT signaling, activated by EML4-ALK phase separation, significantly promotes squamous transition. Integrative study with scRNA-seq and immunostaining identify a plastic cell subpopulation in ALK-rearranged human LUAD showing squamous biomarker expression. Moreover, those relapsed ALK-rearranged LUAD show notable upregulation of squamous biomarkers. Consistently, mouse squamous tumors or LUAD with squamous signature display certain resistance to ALK inhibitor, which can be overcome by combined JAK1/2 inhibitor treatment. This study uncovers strong plasticity of ALK-rearranged tumors in orchestrating phenotypic transition and drug resistance and proposes a potentially effective therapeutic strategy.