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

Henna Kasanen,Mette Ilander,Satu Mustjoki,Micaela Hernberg,Oscar Brück,Siru Mäkelä,Anna Kreutzman,Susanna Juteau,Laura Kohtamäki

doi:10.1007/s00262-020-02497-9

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.

Highlights

Immunotherapies have come to stay in the treatment of advanced melanoma due to their improved efficacy that has translated into superior overall survival compared to conventional therapies such as chemotherapy [1]
From the tumor biopsy taken from a well-responding patient, we found a number of CD4+ T cells secreting granzyme B (GrB), but little to none were found in the biopsy obtained from the non-responder
We hypothesized that natural killer (NK), natural killer T (NKT) and T cells are influenced by PD1 inhibition in metastatic melanoma patients, and that the therapy would potentially affect the immunophenotype

Summary

Introduction

Immunotherapies have come to stay in the treatment of advanced melanoma due to their improved efficacy that has translated into superior overall survival compared to conventional therapies such as chemotherapy [1]. From the recent plethora of novel immune therapies, the checkpoints inhibiting monoclonal antibodies, anti-PD1 and anti-CTLA4 have been promising in the treatment of metastatic melanoma [2, 3], whereas many other are currently undergoing early clinical trials [4]. The inhibition of the PD1 pathway reactivates the anti-tumor T-cell response by blocking the inhibitory signal induced by tumor cells [5]. No comprehensive immunomonitoring of the patients during anti-PD1 has been performed. The in vivo effects of anti-PD1 on other lymphocytes than T cells, such as natural killer (NK) and natural killer T (NKT) cells in cancer patients remain unexplored. NK cells are key effectors in the first line immune defense due to their rapid response to virally infected and tumor cells. NKT cells produce large amounts of cytokines, such as interferon-γ (IFN-γ), which adjust the activation of NK and T cells [8, 9]

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