The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Section Editor for the Case Reports Section, Dr. Alfred Zippelius.
Progressive immune dysfunction with advancing disease stage in renal cell carcinoma by David A. Braun et al
The comprehensive immune landscape of clear cell renal carcinoma (ccRCC) has yet to be characterized at various stages of disease. David A. Braun and colleagues used single-cell RNA (scRNA)-sequencing and single-cell T cell receptor (scTCR)-sequencing on 13 ccRCC tumors to delineate immunobiology across all stages of disease. Nineteen individual T cell populations were identified comprising 8 categories. Cytotoxic CD8+ T cells and CD4+ T cells were enriched in normal tissue and early-stage ccRCC, and terminally exhausted CD8+ T cells with low TCR diversity were enriched in late-stage ccRCC. Trajectory inference analysis fit expression of individual genes along a biological pseudo-timeline/stages of disease model, and supported the differential distribution of these T cell populations in early- and late-stage disease. In the myeloid compartment, 16 individual populations were identified in 6 broader categories, and their trajectories from early stage to late stage ccRCC began as predominantly classical monocytes that then branched to either non-classical monocytes or macrophages. Within the macrophage populations, proinflammatory macrophages were associated with early-stage disease and M2-like anti-inflammatory macrophages were enriched in late-stage tumors. Computational analysis against a repository of ligand-receptor interactions revealed a number of interactions predicted between the exhausted CD8+ T cell population and M2-like macrophages. Some of these predicted interactions involved T cell inhibitory signaling, M2-polarization, cytokine/chemokine signaling, and cell adhesion. The receptors/ligands involved in these signaling pathways were confirmed at the protein level by flow cytometry. The terminal T cell exhaustion/M2-like macrophage interaction gene signature was then analyzed against The Cancer Genome Atlas (TCGA), where it was confirmed to be enriched in late-stage disease and associated with worse outcomes overall.
Why this matters: This study provides a wealth of data that may identify additional signaling pathways to target alone or in combination with current immune checkpoint inhibitors to further enhance antitumor immune responses.
Identification of bacteria-derived HLA-bound peptides in melanoma by Shelly Kalaora et al
Bacteria often colonize in human tumors, however it is not yet known how this affects anti-tumor immunity. Shelly Kalaora and colleagues used 16S rRNA sequencing in combination with human leukocyte antigen (HLA) peptidomics in melanoma tumors to catalogue microbial taxa and immune phenotypes. Sequencing revealed 41 unique bacterial species in 17 melanoma metastases (from 9 patients), with a similarity in the composition of bacteria across samples noted. HLA peptidomics searched against the known proteome profiles of the bacteria identified 248 HLA class I (HLA-I)-associated and 35 HLA class II (HLA-II)-associated peptides. In vitro studies using B cell lines cocultured with bacterial species identified in melanoma tumors confirmed the ability of antigen-presenting cells to present the identified bacterial peptides. Further, it was verified that the bacteria identified were able to enter melanoma cells, whereas control bacteria not identified in the tumor samples had weaker cell invasion. Knockdown of HLA-II transactivator genes and experiments using the less invasive control bacteria (both of which reduced presentation of bacterial peptides) demonstrated that the bacterial peptides identified were bona fide HLA ligands. Many of these bacterial peptides are presented on both antigen-presenting cells and melanoma cells, and many bacterial protein groups had substantial overlap in peptides, demonstrating that some peptides may be more prevalent through presentation ‘hot spots.’ Peptide presentation on B cells resulted in an immunogenic response, with increased interferon-gamma secretion by autologous tumor infiltrating lymphocytes. Altogether, this study identified and characterized bacterial peptide presentation in melanoma tumors, importantly demonstrating the existence of recurrent peptides across bacterial taxa that could be developed as immunotherapeutic targets.
Why this matters: Identifying non-self immunogenic antigens presented by tumor cells suggests the possibility of microbiota-targeted interventions as a strategy for immunotherapy.
NASH limits anti-tumour surveillance in immunotherapy-treated HCC by Dominik Pfister et al
One of the non-viral etiological factors contributing to hepatocellular carcinoma (HCC) is non-alcoholic fatty liver disease (NAFLD) that progresses into non-alcoholic steatohepatitis (NASH). Dominik Pfister and colleagues investigated whether anti-tumor immune responses to anti-PD-1 ICIs are altered in NASH-induced HCC. While local immune cell infiltration can predict improved response to immunotherapy in many tumor types, the enrichment of activated and exhausted CD8+PD1+ T cells seen in mouse models of NASH-induced HCC did not have the same prognostic implications. Here, NASH-HCC-bearing mice treated with anti-PD-1 therapy experienced increased fibrosis and incidence of liver cancer with no regression in lesions. In fact, CD8+ T cells contributed to HCC development, evidenced by reduced liver damage and HCC in mice with NASH with depleted CD8+ T cells. Both mouse and human NASH tissue demonstrated high levels of CD8+PD1+ T cells with a resident-like T cell gene expression signature. A meta-analysis of three randomized controlled phase III immunotherapy trials (CheckMate 459, IMbrave150, and KEYNOTE-240) showed superior response to ICIs in patients with viral HCC compared to non-viral HCC, however this analysis could not account for types of liver disease within the non-viral population. Two independent cohorts of patients with HCC treated with anti-PD-(L)1 therapy found that those with NAFLD had reduced overall survival compared to those with HCC driven by other etiological factors. Together, this study provides mechanistic evidence of aberrant immune activation and surveillance in patients with NASH and NASH-HCC that may preclude benefit to ICI therapy, which warrants further investigation.
Why this matters: No validated biomarkers exist to predict which patients with HCC will benefit from immunotherapy. This study demonstrates that the etiology of HCC may serve as an indicator of response to ICI therapy, which, if validated, could be used in patient selection to improve outcomes in the standard of care setting and for stratification in future clinical trials.
Cytotoxic lymphocytes target characteristic biophysical vulnerabilities in cancer by Maria Tello-Lafoz et al
Myocardin-related transcription factors (MRTFs) regulate the cellular morphology of metastatic tumor cells, including cellular stiffness. Based on the premise that killing of tumor cells by cytotoxic lymphocytes requires rigidity of the target cell to form an immune synapse, Tello-Lafoz and colleagues investigated if metastatic, MRTF-overexpressing cancer cells were more sensitive to immune cell killing. Interestingly, high MRTF signaling is known to be beneficial for metastatic seeding. However, in syngeneic models of murine melanoma (B16F10) and breast cancer (EO771), the metastatic burden of MRTF-overexpressing cells was actually decreased, which suggests a role for the immune system in the prevention of these metastases. Indeed, depletion of CD8+ T cells or NK cells largely increased metastatic seeding of the MRTF-overexpressing cells. Importantly, tumors with overexpression of MRTF did not have higher immune cell infiltration, suggesting that the effect is not due an increase in abundance of lymphocytes, but rather sensitivity to lymphocyte killing. In vitro studies confirmed increased cytotoxic killing of MRTF-overexpressing cells, which was in large part not attributable to isolated molecular components of cytotoxicity, such as perforin, granzyme B, or Fas-ligand. Degranulation was much higher in lymphocytes cocultured with MRTF-overexpressing cells, indicating increased activation. Administering an immune checkpoint inhibitor (ICI) upon transplantation with MRTF-overexpressing cells in mice inhibited metastasis and increased survival compared to WT tumor cells. Interestingly, mining of The Cancer Genome Atlas (TCGA) the authors found a connection between MRTF signaling and RAC-dependent signaling in a subset of melanoma patients, where treatment with anti-CTLA-4 ICIs also improved outcomes. The mechanism behind these findings was demonstrated to be morphology-based as MRTF-overexpression increased stiffness of the tumor cells. When F-Actin (and thus, the rigidity of the cells) was depleted, the lymphocyte activation and cytotoxic effects were reversed. In all, this study provides new mechanistic insights into the mechanical and morphological aspects of cytotoxic lymphocyte mediated tumor cell killing.
Why this matters: This study provides deep insight into microenvironmental aspects of immune surveillance, and also reveals a double-edged sword in malignancy where a mechanism required for metastasis also renders tumor cells more sensitive to cytotoxicity.
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