PD-L1 Expression and Tumor-Infiltrating Lymphocytes Define Different Subsets of MAPK Inhibitor–Treated Melanoma Patients

Abstract

Purpose: To evaluate the expression of tumor PD-L1 and changes in tumor-infiltrating lymphocyte (TIL) populations in patients with metastatic melanoma treated with targeted MAPK inhibitors.Experimental Design: Ninety-three tumors were analyzed from 40 patients treated with a BRAF inhibitor alone (BRAFi; n ¼ 28) or combination of BRAF and MEK inhibitors (Combi; n ¼ 12). Tumors were excised before treatment (PRE), early during treatment (EDT), and at progression (PROG). Immunohistochemical staining was performed for CD4, CD8, CD68, FOXP3, LAG3, PD-1, and PD-L1 and correlated with clinical outcome.Results: Patients' tumors that were PD-L1 positive at baseline showed a significant decrease in PD-L1 expression at PROG (P ¼ 0.028), whereas patients' tumors that were PD-L1 negative at baseline showed a significant increase in PD-L1 expression at PROG (P ¼ 0.008) irrespective of treatment with BRAFi or Combi. Overall PD-L1 expression highly correlated with TIL immune markers. BRAFi-treated patients showed significant increases in CD4 þ , CD8þ , and PD-1 þ lymphocytes from PRE to EDT (P ¼ 0.001, P ¼ 0.001, P ¼ 0.017, respectively), and Combi-treated patients showed similar increases in CD4 þ and CD8 þ lymphocytes from PRE to EDT (P ¼ 0.017, P ¼ 0.021).Conclusions: The addition of MEKi to BRAFi did not result in significant reduction in immune infiltration in EDT biopsies. This provides support for conducting trials that combine MAPKi with immune checkpoint inhibitors in the hope of improving complete and durable response rates. PD-L1 expression at PROG on MAPK inhibitors varied according to baseline expression suggesting that combining MAPKi with immunotherapies concurrently may be more effective in patients with PD-L1 expression and TILs in baseline melanoma samples.

Tumor PD-L1 expression, immune cell correlates and PD-1+ lymphocytes in sentinel lymph node melanoma metastases

“…26 In our cohort of patients, the expression of tumor PD-L1 correlated highly with the presence of intratumoral lymphocyte subsets, including those that were PD-1 positive. These results support previously reported findings by our group and others, 25,26,29 which suggest the presence of lymphocytes that secrete IFN-γ, as well as other co-contributing factors, drives the expression of tumor PD-L1 in an acquired adaptive immune evasion phenomenon. This model is also supported by our finding that patients with positive tumor PD-L1 have a higher median diameter of tumor in their sentinel lymph node compared to patients with tumors that were negative for PD-L1.…”

“…Tumor PD-L1 can also be expressed in a constitutive manner, yet this only accounts for less than 5-10% of tumor PD-L1 positive cases 25,29 and these patients could potentially gain the greatest benefit from specific PD-L1 inhibitors, which show a significant association between tumor or immune cell PD-L1 expression and response to anti-PD-L1 inhibitors. 35 Recurrence free survival (days) Overall Survival (days)…”

“…22, 23 We have previously demonstrated that there is an influx of CD4+ and CD8+ lymphocytes into melanomas of patients treated with BRAF inhibitor alone 24 and more recently with the combination of BRAF and MEK inhibitors. 25 It has also recently been shown that a higher density of peritumoral CD8+ lymphocytes at baseline is predictive of response in patients treated with PD-1 inhibitors. 26 It is currently unknown whether PD-1/PD-L1 inhibitors will improve survival when administered in an adjuvant setting, and whether known predictors of response such as tumor PD-L1 expression 13 and peritumoral CD8+ lymphocytes, 26 which have been identified in advanced stage metastatic melanoma patients treated with PD-1 inhibitors, will also predict responses in the adjuvant setting.…”

Clinicopathologic features associated with efficacy and long‐term survival in metastatic melanoma patients treated with BRAF or combined BRAF and MEK inhibitors

“…The mechanisms responsible for prolonged responses to therapy remain unclear; however, translational data demonstrate immune infiltrates early during treatment, which likely result in a secondary antitumor immune response. [35][36][37] The clinicopathologic correlates of MAPK inhibitor outcomes described here (particularly serum LDH) warrant validation in larger series and may help to inform therapeutic decisions in the future.…”

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

“…118 Importantly, several additional preclinical data confirmed that double blockade of MAPK inhibitors and the PD-1/PD-L1 pathway mounted a synergistic antitumor function. [119][120][121][122] In Kirsten rat sarcoma viral oncogene-mutant NSCLC, investigators pointed out that the MAPK signaling pathway and downstream transcription factor, activator protein-1 are crucial for PD-L1 expression. 123 The MAPK inhibitor might somehow dampen the efficacy of PD-1/PD-L1 inhibitors.…”