Age-associated changes in the immune system may influence the response to anti-PD1 therapy in metastatic melanoma patients

Abstract

Anti-PD1 treatment has improved the survival of metastatic melanoma patients, yet it is unknown which patients benefit from the treatment. In this exploratory study, we aimed to understand the effects of anti-PD1 therapy on the patients' immune system and discover the characteristics that would result in successful treatment. We collected peripheral blood (PB) samples from 17 immuno-oncology-naïve metastatic melanoma patients before and after 1 and 3 months of anti-PD1 therapy. In addition, matching tumor biopsies at the time of diagnosis were collected for tissue microarray. The complete blood counts, PB immunophenotype, serum cytokine profiles, and tumor-infiltrating lymphocytes were analyzed and correlated with the clinical data. Patients were categorized based on their disease control into responders (complete response, partial response, stable disease > 6 months, N = 11) and non-responders (progressive disease, stable disease ≤ 6 months, N = 6). During therapy, the PB natural killer T (NKT) cell frequency, expression of CD25 and CD45RO on cytotoxic natural killer (NK) cells, and serum CXC chemokine levels were significantly increased in responders. Furthermore, higher age together with age-associated characteristics from PB, lower frequency of PB-naïve CD8 + T cells, and elevated levels of serum MCP-4 and OPG were discovered as baseline predictors of treatment response. We therefore propose that in addition to T cells, anti-PD1 treatment is associated with NK-and NKT-cell population dynamics, and that the age-associated characteristics from PB together with older age may contribute to prolonged PFS in anti-PD1-treated melanoma patients.

Clinical Implications of Aberrant PD-1 and CTLA4 Expression for Cancer Immunity and Prognosis: A Pan-Cancer Study

“…Here we examined PD-1 and CTLA4 expression in a large and diverse set of samples from CCLE, which provides gene expression data for future experiments, and from TCGA, which provides genomic and survival data that may be useful for clinical investigations. Consistent with previous reports ( 39 , 40 ), we found that PD-1 was more highly expressed in older cancer patients, indicating that checkpoint inhibitor treatment may more effective in this group. Additionally, Black patients had higher PD-1 and CTLA4 levels than Caucasian or Asian patients, suggesting better outcomes following immunotherapy.…”

Regulation of the human NK cell compartment by pathogens and vaccines

“…14 Increased expression of checkpoint inhibitors including TIM3 and PD-1 has also been observed after repeated malaria exposure with increasing age in endemic populations, 62 again with parallels to the emergence of LAG3 and PD1 + adaptive NK cells after activating receptor (NKp30, NKG2D, NKG2C) or HCMV-mediated activation in vitro. 14 Interestingly, a CD25 + CD45RO + NK cell population has been identified in patients with metastatic melanoma treated with anti-PD-1 62,63 further supporting a potential for progressive differentiation of NK cells in a manner analogous to that seen in T cells. There is also evidence that persistent Mycobacterium tuberculosis infections, and the associated chronic inflammatory response, lead to the emergence of CD45RO + NK cells and enrichment of these cells in the pleural effusion fluid of pulmonary tuberculosis patients.…”

Immune Profile Analysis in Peripheral Blood and Tumor in Patients with Malignant Melanoma

“…As tumor side variables, responders to anti-PD-1 antibody treatment are associated with tumors bearing PD-L1 [ 35 , 36 , 37 ] and MHC-class II [ 38 ]. On the contrary, as a characteristic of host immune cell profiles in responders, a high frequency of CD4 and CD8+ T cells [ 35 , 38 ], NK cells [ 39 ], Th9 [ 40 ], central memory cells [ 41 ], and effector memory T cells [ 42 ] has been observed. IFN-γ is also observed in responders [ 43 , 44 ].…”