The following articles have been recommended for further reading in the field of cancer immunotherapy by Dr. Christian Capitini, Section Editor for the Commentary/Editorials section.
“A reservoir of stem-like CD8+ T cells in the tumor-draining lymph node preserves the ongoing anti-tumor immune response” by Kelli A Connolly et al
The presence of “stem-like” TCF1+ CD8+ T cells (TSL) in tumors is associated with improved outcomes after immunotherapy, yet it is not known how this population overcomes the abundant intratumoral signals driving terminal differentiation. Using neoantigen-expressing KP-NINJA models that mimic the histological, transcriptomic, epigenomic, and genetic features of developing human lung adenocarcinomas, Kelli A Connolly and colleagues followed tumor-specific T cell populations in tumor and draining lymph nodes (dLNs) throughout the course of disease. The proportion of intratumoral terminally differentiated Tim3+ TCF1- PD-1+ CD8+ T cells increased (3.7% to 7.9%) whereas a population of TCF1+ PD-1+ CD8+ T cells remained relatively stable in number from early to late tumor development. In the dLN, by contrast, 65% and 74% of the tumor-specific CD8+ T cells were TCF1+ PD-1+ at the 8 to 10 weeks and 16+ weeks time points, respectively. These TCF1+PD-1+ CD8+ dLN T cells remained phenotypically stable and TIM3- throughout tumor development. Gene expression profiles of TCF1- PD-1hi Tim3+ intratumoral CD8+ T cells showed exhaustion signatures similar to those of exhausted T cells (TEX) in chronic LCMV infection. Using scVelo analyses, which infers differentiation states over pseudotime based on splicing kinetics from transcriptomics data, a progression of tumor-specific T cells toward a terminally differentiated state was observed for the intratumoral populations of cells. In contrast, the differentiated states for naïve and stem-like T cells in dLNs at early and late time points largely overlapped and no consistent direction of differentiation was identified by scVelo analysis. Tumor-specific TSL were not found in spleen, thymus, bone marrow, inguinal, nor mesenteric lymph nodes) and blocking lymphatic migration from dLNs decreased the number of tumor-specific TCF1+ CD8+ T cells but not TCF1- CD8+ T cells in tumor tissue. Analysis of CD8+ T cells derived from treatment-naïve human lung adenocarcinoma (normal and tumor-containing lung and lymph node) recapitulated dynamics of the KP-NINJA models, with normal lymph node CD8+ clusters predominantly TSL-like and TEX-like cell clusters dominating the metastatic lymph node and tumor lung tissues.
Why this matters: The identification of the draining lymph node as a reservoir for stem-like T cells lays the groundwork for new potential therapeutic targets in patients with immunologically cold tumors. Strategies to mobilize TSL cells from the dLN to the tumor and thus maintain TCF1+ PD-1+ T cell populations may help overcome resistance to PD-1 blockade.
MAIT cells regulate NK cell-mediated tumor immunity by Emma V Petley et al
The function of mucosal-associated invariant T (MAIT) cells in anti-tumor immunity is largely unknown with inconsistent reports in the literature to date. Emma V Petley and colleagues demonstrate that regulation of natural killer (NK) cells underlies diverging roles for MAIT cells anti-tumor immune responses. In B16F10 melanoma-bearing MAIT cell-deficient mice, lung metastases and tumor growth were both attenuated. MAIT-deficient mice had increased numbers of natural killer (NK) cells in the lungs, and the NK cells were more frequently cytotoxic. The effects of MAIT deficiency to impair tumor metastasis and growth were NK cell-dependent. Conversely, however, metastases were also decreased when mice were implanted with tumor cells pulsed with MAIT cell antigen 5-OP-RU, leading to MAIT cell activation. The expansion and activation of MAIT cells caused increased secretion of interferon-gamma (IFNy), ultimately leading to increased recruitment and activation of NK cells and macrophages, however, NK cells were necessary for tumor control. Analysis of human tumor transcriptomes in The Cancer Genome Atlas (TCGA) database revealed that signatures associated with high numbers of MAIT cells were associated with worse overall survival in patients that also had expression profiles consistent with high NK cell infiltration. Altogether, this study highlights diverging roles for activated and inactivated MAIT cells in contributing to the immunosuppressive tumor microenvironment.
Why this matters: Activated MAIT cells may promote NK cell-mediated reduction in tumor metastasis and growth, identifying this cell type as a novel therapeutic target to enhancing anti-tumor immune responses.
Genome-scale screens identify factors regulating tumor cell responses to natural killer cells by Michal Sheffer et al
Allogeneic natural killer (NK) cell therapies have demonstrated the ability to facilitate anti-tumor immune responses without the graft-versus-host adverse effects that can occur with T cell therapies. In an effort to maximize effectiveness of NK cell therapies, Michal Sheffer and colleagues utilized high-throughput screening and genome editing techniques to characterize gene expression signatures associated with tumor cell sensitivity to NK cells. Using the profiling relative inhibition simultaneously in mixtures (PRISM) cell line screening approach, tumor cell lines vulnerable to donor-derived NK cell killing were identified. Using CRISPR-mediated genetic screens and gene set enrichment analysis (GSEA) of tumor cell lines, they identified that tumor cells sensitive to NK cell cytotoxicity were enriched for expression of ‘mesenchymal-like’ gene signatures, chromatin remodeling complexes, and B7-H6, an activating ligand for an NK cell receptor. Sensitivity was also associated with as low expression of HLA-E, a major histocompatibility complex (MHC) class I molecule, and other genes encoding products involved in antigen presentation. Analyses of The Cancer Genome Atlas (TCGA) database of cell line transcripts confirmed that tumors of mesenchymal origin have lower expression of genes involved in antigen presentation, and negative correlation between expression levels of HLA-E and chromatin remodeling genes. Interestingly, the transcriptional signatures associated with response to NK cell-mediated cytotoxicity also were associated with lack of response to checkpoint blockade in samples from multiple cohorts of patients with melanoma and leiomyosarcoma treated with immune checkpoint inhibitors.
Why this matters: This study not only identified tumor cell characteristics associated with sensitivity to NK cell-mediated cytotoxicity, which can be used to identify patients that will benefit from NK cell therapy, but also suggests that NK cell therapy may be an effective treatment for checkpoint inhibitor-resistant cancers.
“CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial” by Jay Y Spiegel et al
Antigen loss is a well-characterized escape mechanism for B cell acute lymphoblastic leukemia (B-ALL) after chimeric antigen receptor (CAR) T cell therapy, but resistance in large B cell lymphoma (LBCL) is not well understood. After identifying the emergence of CD19-/lo LBCL associated with resistance to axicabtagene ciloleucel in a high proportion of patients in their single-institution cohort, Jay Y Spiegel et al evaluated a bispecific CAR with tandem CD19 and CD22 scFV recognition domains and a 4-1BB costimulatory domain (CD19-22.BB.z) for the treatment of relapsed/refractory B-ALL and LBCL in a phase I trial. The primary endpoints were feasibility of manufacturing and safety. The recommended phase II dose of 3x106 CAR+ cellskg-1 was successfully manufactured in a closed system CliniMACS Prodigy with 97% of products meeting protocol-specified dose. Of the 39 patients who were enrolled, (n= 17 with B-ALL) and (n= 22 LBCL), 38 received infusion of the bispecific CAR T cells. One dose-limiting toxicity occurred during the trial. Cytokine release syndrome occurred in 76% of patients (5% grade ≥3) and neurotoxicity in 37% of patients (11% grade ≥3). The overall response rate for patients with LBCL was 62%, with a 6-month PFS rate of 29% (95% CI, 12−48%). Response rates were higher in the B-ALL cohort, with 82% of patients achieving minimal residual disease negative complete responses. At time of progression after CD19-22.BB.z-CAR therapy, CD19-/lo disease was observed in 29% of patients LBCL and 50% of patients with B-ALL. Notably, CD22 loss was rarely observed. In vitro, intracellular cytokine secretion by the CD19-22.BB.z CAR T cells was decreased with CD22 stimulation. Additionally, TNF-alpha and IL-2 secretion after stimulation with CD22 was lower for the bispecific CAR T cells than that of monospecific anti-CD22 CAR T cells constructed with an identical scFV, costimulatory, and hinge domain.
Why this matters: The identification of the emergence of CD19-/lo disease with CD22 expression maintained as a resistance mechanism to bispecific anti-CD19/CD22 CAR T cell therapy for LBCL further underscores challenges in developing and optimizing novel CAR constructs. This study further identifies putative biomarkers for CAR T cell potency, including CD4+ composition of the manufactured product and cytokine production in vivo, that could be used for future drug development.
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