Impact of anti-PD-1 on T-cells....information that may lead to making anti-PD-1 more effective!!!

Wanted to share these posts before I embark on my new adventure.  These abstracts do not include anything that is directly impacting the care of melanoma patients today....but are hopeful in the sense that smart peeps are continuing to look at what happens in melanoma peeps for whom anti-PD-1 works.  In the end, I am certain that this will result in improved efficacy for all!!!

Activation of central/effector memory T cells and Th1 polarization in malignant melanoma patients treated with anti-PD-1 antibody. Yamaguchi, Mishima, Ohmura, et al.  Cancer Sci. 2018 Aug 1.

Human anti-programmed death-1 (PD-1) antibody possesses the capability to revitalize host T cells and has been an effective therapy for metastatic malignant melanoma (MM). However, the precise subsets of T cells predominantly activated by anti-PD-1 have not yet been clarified. In this study, peripheral blood mononuclear cells obtained from MM patients scheduled to receive anti-PD-1 (nivolumab) therapy, and healthy subjects (HS), were systematically examined by flow cytometry to identify changes in the proportion of immune cell subsets. Compared with HS, MM patients prior to therapy demonstrated an increased proportion of activated CD8+ T cells with effector memory phenotypes (Tem), and PD-1 positive subsets of CD4+ central memory T cells (Tcm) and Th17 cells. After a single course of anti-PD-1 therapy, MM patients showed an increase in activated Tem and Tcm subsets of CD4+ and CD8+ T cells, and activated Th1 plus Tfh1 cells. There was no consistent change in the proportion of Tfh cells, B cells, natural killer cells, or dendritic cells. The observed activated phenotypes were attenuated during the course of therapy; however, regulatory T cells belonging to the CD3+CD4+CD45RO+CD25high fraction increased at the disease progression. Taken together, anti-PD-1 therapy modulates systemic immune reactions and exerts anti-tumor effects, not only by revitalizing Tem and Tcm of CD4+ and CD8+ T cells, but also via a shift to a Th1 phenotype.

Resident Memory-Like Tumor-Infiltrating Lymphocytes (TIL_RM): Latest Players in the Immuno-Oncology Repertoire. Smazynski, Webb.  Front Immunol. 2018 Jul 26 

Resident memory T cells (T_RM) are a recently identified subset of long-lived memory T cells that are characterized in terms of their unique surface phenotype combined with a non-recirculating pattern of localization to non-lymphoid, peripheral tissues. T_RM have quickly become a key area of focus in understanding immune responses to microbial infection in so-called "barrier" tissues, and appear to be particularly critical for protection against repeat exposure at the same site. More recently, tumor-infiltrating T cells with canonical T_RM features are being identified in human cancers, in particular cancers of epithelial origin, and their presence is broadly found to be associated with favorable long-term prognosis. Moreover, recent studies have shown that these "resident memory-like" tumor-infiltrating lymphocytes (referred to herein as TIL_RM) are uniquely activated in melanoma patients undergoing PD-1 directed checkpoint blockade therapy. Accordingly, there is much interest at present regarding the biology of these cells and their precise role in anti-cancer immunity. Herein, we review the current state of the literature regarding TIL_RM with a specific emphasis on their specificity, origins, and relationship to conventional pathogen-specific T_RM and speculate upon the way(s) in which they might contribute to improved prognosis for cancer patients. We discuss the growing body of evidence that suggests TIL_RM may represent a population of bona-fide tumor-reactive T cells and the attractive possibility of leveraging this cell population for future immunotherapy.

Decreased Suppression and Increased Phosphorylated STAT3 in Regulatory T-cells are Associated with Benefit from Adjuvant PD-1 Blockade in Resected Metastatic Melanoma.  Woods, Ramakrishnan, Laino, ..., Weber.  Clin Cancer Res. 2018 Aug 21.

PD-1 blockade induces durable responses in patients with metastatic melanoma and prolongs relapse-free survival in patients with resected melanoma; however, current biomarkers do not consistently associate with patient responses. In this study we investigated the impact of nivolumab therapy on peripheral blood Tregs and its relation to patient outcomes.

Peripheral blood Tregs and conventional CD4+ T-cells from patients with resected high-risk melanoma treated with adjuvant nivolumab were assessed for gene expression changes by RNA-seq. Percentages of circulating Tregs and phosphorylated-STAT3 (pSTAT3) expression levels were assessed by flow cytometry and validated in an independent cohort of active disease patients. Suppressive function of Tregs was assessed in allogeneic mixed lymphocyte reactions.

Tregs from non-relapse patients had increased expression of proliferation associated genes. An increase in the proportion of circulating Tregs and pSTAT3 expression and a reduction in Treg suppressive capacity were observed in non-relapsing, but not relapsing patient samples 13 weeks after starting treatment. In vitro blockade of PD-1 increased Treg percentages and pSTAT3 expression, and reduced Treg suppressive function. PD-1 blockade also led to IL-10 production by T-cells, resulting in higher Treg proliferation. The addition of a STAT3 inhibitor ameliorated the increase in Tregs, enhanced suppressive function, and decreased T-cell IL-10 production in vitro.

These results demonstrate that induction of pSTAT3, reduced suppressive function, and a paradoxical increase in Treg proliferation are novel correlates of patient benefit from PD-1 blockade.

I've placed in bold what I think most pertinent.  Hang tough ratties.  My best to each of you. - c