The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Clinical/Translational Cancer Immunotherapy Section Deputy Editor, Claudia Palena, PhD.
“Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers” by Myriam Chalabi et al
Checkpoint blockade with anti-PD-1 and anti-CTLA-4 has become the standard of care for patients with mismatch repair-deficient (dMMR) metastatic colorectal cancers, yet response rates have been disappointing in patients with mismatch repair proficient (pMMR) tumors. Based on impressive early reports of deep pathological responses with PD-1/CTLA-4 blockade in the neoadjuvant setting for melanoma, lung cancer and bladder cancer, Myriam Chalabi and colleagues conducted an exploratory study of checkpoint inhibitor therapy for early stage colon cancer, including 21 participants with dMMR tumors and 20 with pMMR tumors. In the trial (NICHE Study; ClinicalTrials.gov: NCT03026140), after a safety run-in of 3 patients who received nivolumab monotherapy, 37 patients were treated with a single dose of anti-CTLA-4 ipilimumab and two doses of anti-PD-1 nivolumab before surgery. Of 17 the patients in the pMMR group, 8 were randomized to also receive celecoxib. Of the 35 evaluable patients who received ipilimumab + nivolumab, 100% of patients with dMMR tumors (20/20) achieved a pathological response, with 19 major pathological responses ( ≤10% residual viable tumor), and 12 pathological complete responses. Among the group with pMMR tumors, 4/15 (27%) achieved pathological responses, with 3 major pathological responses and 1 partial response. Importantly, correlation between radiological assessment of response and histopathological findings was strikingly poor. Treatment was well tolerated, with only five patients experiencing grade 3-4 treatment-related AEs, all of which were successfully managed or spontaneously resolved. Extensive analyses of the tumor microenvironment revealed significant increases in TCR clonality (P = 0.007), IFN-γ score (P = 0.001), and CXCL13 expression (P = 0.01) in all pMMR tumors after treatment, however only pre-treatment CD8+PD-1+ T cell infiltration was predictive of response to therapy in this group. If these findings are validated in larger studies, neoadjuvant immunotherapy could become an important option for the treatment of some early stage colon cancers.
“Intratumoral CD4+ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer” by David Y Oh et al
No validated biomarkers exist to predict response to PD-1 blockade for bladder transitional cell carcinoma (TCC). To interrogate the contributions of T cell subsets to response to checkpoint inhibition, David Y Oh et al performed droplet single-cell RNAseq and paired T cell receptor (TCR) sequencing on 30,604 T cells from both tumor and adjacent non-malignant tissue from seven patients with muscle-invasive bladder cancer, four of whom had received anti-PD-L1 atezolizumab, two of whom were untreated as per standard of care, and one who was treated with carboplatin and gemcitabine. Clustering analysis grouped the CD8+ T cells into 11 different states, but not one single cluster showed significant enrichment between tumor and normal tissue. By contrast, significant compartment-specific enrichment was observed for several functional subsets of CD4+ T cells, including central-memory CD4+ T cells, which were more common in healthy tissue, and checkpoint-expressing Tregs, which made up the majority of tumor-infiltrating CD4+ lymphocytes. TCR sequencing of 11,081 CD4+ T cells and 5,779 CD8+ T cells revealed a more restricted receptor repertoire within the tumor compared to adjacent healthy tissue. An important contributor to this repertoire restriction, specifically for CD4+ T cells, was clonal expansion of several distinct regulatory T cell states with differing levels of immune checkpoint expression. Strikingly, in addition to the preponderance of regulatory CD4+ T cells, fully 15% of the tumor-infiltrating CD4+ T cells expressed cytolytic effector molecules. Two cytotoxic CD4+ T cell states were observed: one co-expressed high levels of granzyme B, perforin, and granule-associated proteins, and the other expressed high levels of granzyme K and lower levels of granule-associated protein NKG7. Sorted CD4+ T cells expanded ex-vivo with IL-2 lysed autologous tumor cells in vitro, an effect that was enhanced when Tregs were depleted. Using hierarchical clustering, a composite gene expression signature specific for proliferating cytotoxic CD4+ T cells was predictive for response to therapy in bulk pre-treatment tumor RNA-seq data from 244 patients from the phase II IMvigor210 trial of atezolizumab for metastatic bladder cancer.
“PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer” by Soyoung A Oh et al
Recent observations have highlighted the contributions of myeloid lineage cells in regulating T cell anti-tumor immunity, including the demonstration that interactions between PD-L1 and B7-1 on antigen presenting cells (APCs) sequester available ligand for PD-1 binding. Soyoung A Oh and colleagues reveal greater insight into the relative contributions of macrophages and dendritic cells in generating an immunosuppressive tumor microenvironment via signaling through the PD-1/PD-L1 axis. In murine models of PD-L1-deficient MC38 (ensuring that infiltrating lymphocytes are the sole source of PD-L1 in the microenvironment), CD11b+CD64+ macrophages were the dominant myeloid infiltrate. In the tumors, CD11b+CD64+ macrophages accounted for approximately 75% of PD-L1 on myeloid cells, whereas less than 2% of total PD-L1 expression was found on the CD64− population of CD11c+MHCII+ cells, which includes cross-presenting dendritic cells (DCs). Despite the relative scarcity of PD-L1+ DCs, this population was critical for CD8+ T cell mediated anti-tumor immunity. Mice with a compartment-specific PD-L1 deficiency on DCs (PD-L1ΔDC) restricted tumor growth as effectively as total PD-L1 knockout animals for MC38 tumors and two different PD-L1-proficient models. Notably, deletion of PD-L1 specifically in macrophages did not lead to as effective tumor control compared to DC-specific or total PD-L1 knockout. At both early and late time points after tumor seeding, CD8+ T cells from both total PD-L1 knockout and PD-L1ΔDC mice (both of which controlled tumor growth) showed comparable profiles of highly activated cells coexpressing inhibitory receptors indicative of an exhausted phenotype, suggesting that the exhaustion phenotype may not necessarily reflect a decrease in overall antitumor immunity. The findings reveal new insight into the mechanisms by which immune checkpoints on immune cells regulate antitumor immune activity.
“High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade” by Kobe C Yuen et al
Elevated levels of the proinflammatory chemokine and chemoattractant for myeloid leukocytes IL-8 have been reported as correlating with reduced response to PD-1 blockade in small cohorts of patients with melanoma and non-small cell lung cancer. To comprehensively evaluate a role for IL-8 in determining outcomes after checkpoint inhibition, Kobe C Yuen et al analyzed plasma IL-8 levels and IL8 gene expression in peripheral blood mononuclear cells (PBMCs) and tumors of patients treated with the anti-PD-L1 antibody atezolizumab from multiple randomized trials including 1,445 total patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma mRCC. In the single-arm phase II IMvigor210 study for mUC, higher baseline plasma IL-8 was significantly associated with worse overall survival (OS), and the association remained on multivariate analysis. Baseline IL-8 was significantly associated with worse OS across treatment arms in the randomized phase III IMvigor211 trial for patients with mUC who had received prior platinum therapy, and in patients treated with atezolizumab in the randomized phase II IMmotion150 trial for previously untreated mRCC. On-treatment increases in plasma IL-8 significantly predicted worse outcomes with atezolizumab treatment. Single-cell RNAseq of baseline PBMCs from both responders and nonresponders from IMvigor210 revealed a greater proportion of IL8-producing myeloid and lymphoid cells, and higher overall expression of IL8 in the nonresponders. Across trials, high IL8 gene expression in PBMCs was significantly associated with poor OS after atezolizumab monotherapy (the association was not significant in the combination regimen arms of IMmotion150 where atezolizumab was combined with bevacizumab or sunitinib). The findings provide rationale for pursuing the development of IL-8-blocking agents to potentially enhance the efficacy of checkpoint inhibitors.
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