Divergent Effects of Anti-CTLA4 and Anti-PD1 Blockade in the Tumor Microenvironment of Melanoma Metastases

The success of anti-CTLA4 or anti-PD1 immune checkpoint inhibitors varies widely in melanoma, with the individual modes of action in tumors and treatment-specific biomarkers still being explored. We analyzed pre- and on-treatment tumor samples from melanoma patients treated with anti-CTLA4 or anti-PD1 to characterize immune cell infiltration and molecular pathways in the tumor microenvironment and correlate these findings with treatment response and survival. We observed a prominent role for immune cell infiltration in the tumor microenvironment (TME) for clinical benefit from anti-PD1 therapy, in contrast to anti-CTLA4 therapy. A higher degree of infiltration with CD3+ T cells (p = 0.046), PD1+ (p = 0.002), and INOS+ (p = 0.042) cells was significantly associated with disease control on anti-PD1 treatment. Whereas, a higher degree of infiltration with CD138+ B cells was significantly associated with longer progression-free survival (p = 0.048, HR: 0.301 (95% CI: 0.092–0.989)). The association between immune cell infiltration, TCR richness in tumor samples, and treatment outcomes was even more striking in on-treatment biopsies from patients receiving anti-PD1 treatment. An enrichment of the immunoglobulin signature in on-treatment tumor samples was observed in responding patients. The study highlights the importance of pre-existing immune infiltration in the TME, particularly B cell infiltration, for anti-PD1 success in melanoma patients.