The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC’s Guidelines and Consensus Statements Section Editor, Robert L. Ferris, MD, PhD.
“Clonal replacement of tumor-specific T cells following PD-1 blockade” by Kathryn E. Yost et al.
Checkpoint inhibitors function through the impairment of inhibitory receptors on T-cells. In this way, immunotherapy with checkpoint inhibitors can reverse T-cell exhaustion and enhance anti-tumor immune responses. However, the origin of the T-cell populations responsible for this new anti-tumor response is unclear. In this study, Yost et al. attempt to determine if post-PD-1 blockade T-cell responses are due to reactivation of existing anti-tumor T-lymphocytes, or due to novel T-cell recruitment. Through the use of single-cell RNA and T-cell receptor sequencing on cells taken from carcinomas, T-cell populations can be compared pre- and post-PD-1 blockade. The results of these comparisons suggest that enhanced anti-tumor responses post-PD-1 blockade are likely due to the expansion of novel T-cell populations, and that the reinvigoration of existing, exhausted T-cell populations in response to checkpoint inhibition may be limited.
“WNT/β-catenin pathway activation correlates with immune exclusion across human cancers” by Jason J. Luke et al.
Tumors which exhibit T-cell inflammation are more likely to respond to checkpoint inhibitor therapy. It is known from studies in melanoma that signaling through the WNT/β-catenin pathway can be responsible for a lack of T-cell infiltration within the tumor, but it is not clear if this immune exclusion is mediated by WNT/β-catenin signaling in other types of malignancies. Luke et al. utilize gene expression data from The Cancer Genome Atlas to define states of T-cell inflammation across multiple cancer types. Comparison of gene expression in T-cell inflamed tumor, non-T-cell inflamed tumor, and non-tumor tissue samples enabled characterization of common factors to the non-T-cell inflamed tumor phenotype. Data from this analysis suggests that rates of T-cell inflammation depend on the type of tumor, and support the hypothesis that WNT/β-catenin signaling is inversely correlated to levels of T-cell inflammation within the tumor.
“Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response” by Peng Jiang, Shengqing Gu, Deng Pan et al.
Despite the clinical successes of immune checkpoint blockade, a significant portion of patients do not respond to this therapy. Methodologies that would allow prediction of response to immune checkpoint therapy could provide clinical benefit by enabling identification of the treatment most likely to promote tumor response and survival. Jiang, Gu, and Pan et al. develop a computational framework, known as Tumor Immune Dysfunction and Exclusion (TIDE), to find factors that influence immune exclusion or immune dysfunction and, ultimately, modulate patient response to immune checkpoint blockade. Through the integration of data from 33, 197 samples, the study identified gene signatures associated with immune exclusion and dysfunction. These gene signatures can be used to predict the probability of immune checkpoint blockade benefit, and to predict tumor resistance to checkpoint inhibitors.
“Tumor microbiome diversity and composition influence pancreatic cancer outcomes” by Erick Riquelme, Yu Zhang et al.
Despite the lethality of the disease, a small portion of patients diagnosed with pancreatic adenocarcinoma (PDAC) enjoy long-term survival after resection. The factors influencing long-term survival are largely unknown. Based on the observation that survivors of PDAC tend to exhibit evidence of diverse neoantigens with homology to peptides found in infectious disease, Riquelme and Zhang et al. hypothesized that the tumor microbiome could influence outcomes in patients with PDAC. Through 16s rRNA sequencing, tumor microbiomes were taxonomically profiled and compared based on bacterial diversity and overall survival. As hypothesized, patients with more diverse tumor microbiomes exhibited significantly longer overall survival, and tumor microbiomes in long-term survivors were significantly different from those in short-term survivors. The study also demonstrated that portions of the gut microbiome are shared with the pancreatic tumor microbiome, and performed fecal transplants in mouse models of pancreatic cancer, which altered tumor growth rates. These results suggest that the tumor microbiome has significant influence on patient outcomes, and that manipulation of the gut microbiome may, in turn, alter the tumor microbiome.
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