The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC’s Basic tumor immunology Section Editor, Cornelis J.M. Melief, MD, PhD.
“CD24 signaling through macrophage Siglec-10 is a target for cancer immunotherapy” by Amira Barkal et al.
Monoclonal antibodies against anti-phagocytic cancer cell-surface markers often don’t elicit durable responses, suggesting the existence of additional, unknown “don’t eat me” signals expressed by some tumors. Barkal et al. identify a new potential immunotherapeutic target in CD24-mediated inhibition of the innate immune system, which they show allows cancer cells to avoid clearance by Siglec-10 expressing macrophages. Blockade of CD24 with monoclonal antibodies resulted in significant reduction of tumor growth as well as increased survival time in xenograft models of breast cancer. Genetic deletion of CD24 led to increased infiltration by tumor-associated macrophages in mice, and a substantial reduction in tumor growth, which was abrogated upon macrophage depletion. Furthermore, blockade of Siglec-10 in vitro, as well as deletion of the SIGLEC10 gene augmented the phagocytic ability of macrophages co-cultured with CD24 positive MCF-7 breast cancer cells. RNA-sequencing data from The Cancer Genome Atlas and the Therapeutically Applicable Research to Generate Effective Treatment Program revealed broad upregulation of CD24 in a variety of tumors, most prominently in ovarian cancer, triple-negative breast cancer, and estrogen- and progesterone-positive breast cancers. This study defines CD24-Siglec as an innate immune checkpoint and potential therapeutic target in ovarian and breast cancers.
“T-Scan: a genome-wide method for the systematic discovery of T cell epitopes” by Toasz Kula et al.
Understanding the targets of T cell responses is vital for harnessing and modulating cytotoxic T lymphocytes for cancer immunotherapy. Kula et al. developed a high-throughput, genome-wide platform to discover the antigens productively recognized by such T cells. Importantly, the platform, called T-Scan, leverages genome-wide libraries encoding human or pathogen proteomes that are processed and presented on endogenous MHC-I molecules, adding confidence that the identified antigens are physiologically relevant in vivo. In T-Scan, target cells express a novel fluorescent reporter that becomes activated upon cleavage by granzyme B as well as a library of lentiviral-delivered antigens, which are processed and presented by MHC-I. Granzyme B secretion is a functionally relevant readout of T cell activation that allows for the specific isolation of target cells that have received cytotoxic granules via fluorescence-activated cell sorting and next-generation sequencing allows for identification of cognate antigens. After platform validation in the context of cytomegalovirus antigens, with screens of T cell receptors (TCRs) of known specificity and primary T cells expanded against a known antigen, T-Scan identified two additional human proteins recognized by the self-reactive MAGE-A3 TCR, PLD5 and FAT2. The platform has multiple potential applications to cancer immunology including profiling of neo-antigen reactivities in patient tumor-infiltrating lymphocytes, genome-wide identification of targets of orphan TCRs and screening of therapeutic TCRs for off-target reactivities that could cause toxicity.
“Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis” by Max Wellenstein et al.
Systemic inflammation with high neutrophil-to-lymphocyte ratios are hallmarks of poor prognosis in cancer patients. To uncover the cancer-cell-intrinsic mechanisms that drive neutrophilic inflammation, Wellenstein et al. studied 16 genetically engineered mouse models representing most subtypes of human breast cancer, including ductal and lobular carcinoma, estrogen-receptor positive, HER2+, triple-negative and basal-like, each carrying different tissue-specific mutations. The models with the highest levels of systemic neutrophils, especially those with pronounced populations of cKIT+ neutrophils, all had tumors with p53 deletions. Tumors with p53 deletions displayed elevated WNT-related gene expression as well as increased expression of non-phosphorylated β-catenin. Pharmacological blockade of WNT signaling with LGK974 (an acyltransferase inhibitor that disrupts WNT-ligand secretion) led to reductions in total neutrophils and cKIT+ neutrophils in mice bearing p53-deficient tumors. Additionally, although blockade of WNT signaling did not affect primary tumor growth, LGK974 treatment did dramatically reduce lung metastases. These results suggest that targeting WNT signaling could be a promising strategy to prevent metastases in the treatment of patients with p53-deficient breast tumors.
“Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial” by Leoni Voorwerk et al.
Only around 5% of patients with triple-negative breast cancer respond to PD-1/PD-L1 blockade. Drawing upon preclinical research suggesting immunomodulatory properties for chemotherapy and radiation, Voorwek et al. set out to test whether conventional treatments can turn tumors from “cold” to “hot,” modulating the microenvironment prior to PD1-PD-L1 blockade. In the first stage of an adaptive, non-comparative phase 2 trial, 67 patients with metastatic triple-negative breast cancer were randomized to nivolumab alone without induction, or nivolumab preceded by either 2-week low-dose induction, irradiation, cyclophosphamide, cisplatin, or doxorubicin. Overall, the objective response rate was 20%, with the majority of responses observed in the cohorts who first received cisplatin (ORR 23%) or doxorubicin (ORR 35%) prior to nivolumab. Biopsies revealed higher tumor-infiltrating lymphocytes and CD8+ T cell counts with nivolumab treatment among responders compared to non-responders, as well as elevated expression of immune-related genes. On the basis of Simon’s two-stage design, the doxorubicin cohort is currently expanded in stage II of the trial. This study provides some of the first clinical evidence that induction with cisplatin or doxorubicin can prime tumors for response to PD-1 blockade.
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