Dynamic Changes in PD-L1 Expression and Immune Infiltrates Early During Treatment Predict Response to PD-1 Blockade in Melanoma

Abstract

Disruption of PD-L1/cytotoxic T-cell PD-1 signaling by immune checkpoint inhibitors improves survival in cancer patients. This study sought to identify changes in tumoral PD-L1 expression and tumor-associated immune cell flux with anti-PD-1 therapies in patients with melanoma, particularly early during treatment, and correlate them with treatment response. Forty-six tumor biopsies from 23 patients with unresectable AJCC stage III/IV melanoma receiving pembrolizumab/nivolumab were analyzed. Biopsies were collected prior to (PRE, = 21), within 2 months of commencing treatment (EDT, = 20) and on disease progression after previous response (PROG, = 5). Thirteen patients responded (defined as CR, PR, or durable SD by RECIST/irRC criteria), and 10 did not respond. PRE intratumoral and peritumoral PD-1 T-cell densities were sevenfold ( = 0.006) and fivefold higher ( = 0.011), respectively, in responders compared with nonresponders and correlated with degree of radiologic tumor response ( = -0.729, = 0.001 and = -0.725, = 0.001, respectively). PRE PD-L1 expression on tumor and macrophages was not significantly different between the patient groups, but tumoral PD-L1 and macrophage PD-L1 expression was higher in the EDT of responders versus nonresponders ( = 0.025 and = 0.033). Responder EDT biopsies (compared with PRE) also showed significant increases in intratumoral CD8 lymphocytes ( = 0.046) and intratumoral CD68 macrophages ( = 0.046). Higher PRE PD-1 T cells in responders suggest active suppression of an engaged immune system that is disinhibited by anti-PD-1 therapies. Furthermore, immunoprofiling of EDT biopsies for increased PD-L1 expression and immune cell infiltration showed greater predictive utility than PRE biopsies and may allow better selection of patients most likely to benefit from anti-PD-1 therapies and warrants further evaluation. .

Durable intracranial and extracranial response to nivolumab with appearance of secondary resistance in a heavily pretreated patient with head and neck cancer

“…In contrast, it is well known that PD‐L1 expression in cancer is a dynamic phenomenon that is positively or negatively modulated by disease evolution and treatments . Indeed, tumors from responding patients treated with immunotherapy show early increases in immune infiltrating cells when rebiopsied . Although we are unaware of the mutational burden of the tumor of our patient, it is presumably high given the history of prolonged heavy smoking and alcohol consumption .…”

“…PD-L1 measured in tumor cells achieves 60% (I,J) infiltrating cells when rebiopsied. 13 Although we are unaware of the mutational burden of the tumor of our patient, it is presumably high given the history of prolonged heavy smoking and alcohol consumption. 1,4 Thus, nivolumab could be fairly viewed as the sole executive arm of the response seen in our patient.…”

Immunotherapy for genitourinary tumors

“…First, several clones of anti-PD-L1 antibodies for IHC exist and their cut-off values are variable. 40,41 Second, PD-L1 is dynamic marker affected by concentration of IFN-c in the tumor microenvironment, 42 Third, the investigation target of PD-L1 expression is variable with the studies because PD-L1 is expressed in both tumor cells and immune cells. 43 Fourth, PD-L1 expression level is discordant between the primary tumors and metastatic sites, and is heterogeneous even in tumors.…”

Specific expression of PD‐L1 in RELA‐fusion supratentorial ependymoma: Implications for PD‐1‐targeted therapy

“…These agents are now approved in certain adult tumors, such as melanoma. 8 With respect to CNS tumors, there is evidence in adult glioblastoma that PD-1's interaction with PD-L1 contributes to the profound immunosuppression seen in this tumor. 5 Our lab has shown that EPNs have significant infiltration of immune cells.…”