BACKGROUND: Hormone receptor-positive (HR+) breast cancer responds poorly to immune checkpoint inhibitors (ICIs). In some settings, radiation therapy (RT) has been shown to mediate immunostimulatory effects and promote ICI sensitivity. METHODS: We investigated whether hypofractionated RT may be successfully combined with ICIs in a mouse model of multifocal, metachronous HR+ mammary carcinogenesis. We hypothesized that focal RT targeting the first detectable (primary) tumor combined with ICIs may generate effective immunity, delaying the development of new lesions. RESULTS: Focal RT in various doses and fractionations limited primary tumor growth, with an optimum for a 20-Gy × 2 regimen (ablative in approximately 90% of mice). The degree of primary disease control, however, did not necessarily correlate with overall survival extension because of changes in the development of new neoplastic lesions contributing to global tumor burden. Adding a PD-1 blocker to focal RT delivered in a 10-Gy × 3, 20-Gy × 2, or 8-Gy × 6 regimen failed to alter overall survival extension enabled by RT alone. Similar results were obtained with a CTLA4 blocker, an IL-1β inhibitor, and a PD-1 blocker plus recombinant FLT3LG when combined with the 10-Gy × 3 regimen. CONCLUSIONS: In this model of HR+ mammary carcinogenesis, RT to the primary tumor ameliorates overall survival (to an extent based on dose and fractionation). Increasing local control through RT alone or RT plus immunotherapy beyond a hitherto undefined threshold, however, does not necessarily inhibit the development of subsequent nonirradiated neoplasms and hence does not necessarily provide extra overall survival benefits.

• MeSH
• Programmed Cell Death 1 Receptor antagonists & inhibitors   MeSH
• Mammary Neoplasms, Experimental * therapy   MeSH
• Dose Fractionation, Radiation MeSH
• Radiation Dose Hypofractionation MeSH
• Immunotherapy * methods   MeSH
• Immune Checkpoint Inhibitors * pharmacology   therapeutic use   MeSH
• Combined Modality Therapy MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Breast Neoplasms * pathology   therapy   MeSH
• Receptors, Estrogen metabolism   MeSH
• Receptors, Progesterone metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Programmed Cell Death 1 Receptor MeSH
• Immune Checkpoint Inhibitors * MeSH
• Receptors, Estrogen MeSH
• Receptors, Progesterone MeSH

The mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an open conundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefits of immune checkpoint inhibitors or chemotherapy in eight retrospective cohorts of cancer patients and in tumor-bearing mice. The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and on the metabolic and immune host-microbiota interaction at baseline allowing CD8+ T cell activation without exhaustion. Various strains of Christensenella minuta selectively boost the anti-cancer efficacy of ILDR and PD-L1 blockade, allowing emigration of intestinal PD-L1-expressing dendritic cells to tumor-draining lymph nodes. An interventional phase 2 study provides the proof-of-concept that ILDR can circumvent resistance to first- or second-line immunotherapy in cancer patients. Prospective clinical trials are warranted to define optimal dosimetry and indications for ILDR to maximize its therapeutic potential.

• Keywords
• Christensenella minuta, bile acids, cancer, dendritic cells, gut microbiota, metabolomics, radiotherapy, tumor immunosurveillance,
• MeSH
• B7-H1 Antigen * antagonists & inhibitors   MeSH
• CD8-Positive T-Lymphocytes immunology   MeSH
• Immunotherapy methods   MeSH
• Immune Checkpoint Inhibitors * therapeutic use   pharmacology   MeSH
• Humans MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Neoplasms * immunology   pathology   therapy   radiotherapy   drug therapy   MeSH
• Retrospective Studies MeSH
• Intestines * radiation effects   immunology   MeSH
• Gastrointestinal Microbiome radiation effects   immunology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• B7-H1 Antigen * MeSH
• CD274 protein, human MeSH Browser
• Immune Checkpoint Inhibitors * MeSH

LTX-315 is a nonameric oncolytic peptide in early clinical development for the treatment of solid malignancies. Preclinical and clinical evidence indicates that the anticancer properties of LTX-315 originate not only from its ability to selectively kill cancer cells, but also from its capacity to promote tumor-targeting immune responses. Here, we investigated the therapeutic activity and immunological correlates of intratumoral LTX-315 administration in three syngeneic mouse models of breast carcinoma, with a focus on the identification of possible combinatorial partners. We found that breast cancer control by LTX-315 is accompanied by a reconfiguration of the immunological tumor microenvironment that supports the activation of anticancer immunity and can be boosted by radiation therapy. Mechanistically, depletion of natural killer (NK) cells compromised the capacity of LTX-315 to limit local and systemic disease progression in a mouse model of triple-negative breast cancer, and to extend the survival of mice bearing hormone-accelerated, carcinogen-driven endogenous mammary carcinomas. Altogether, our data suggest that LTX-315 controls breast cancer progression by engaging NK cell-dependent immunity.

• Keywords
• CTLA4, MPA/DMBA-driven mammary carcinomas, PD-1, TS/A cells, cDC1s, immune checkpoint inhibitors,
• MeSH
• Killer Cells, Natural MeSH
• Immunotherapy MeSH
• Humans MeSH
• Mice MeSH
• Tumor Microenvironment MeSH
• Oligopeptides * MeSH
• Triple Negative Breast Neoplasms * therapy   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• LTX-315 MeSH Browser
• Oligopeptides * MeSH

Accumulating evidence indicates that immune checkpoint inhibitors (ICIs) can restore CD8+ cytotoxic T lymphocyte (CTL) functions in preclinical models of acute myeloid leukemia (AML). However, ICIs targeting programmed cell death 1 (PDCD1, best known as PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4) have limited clinical efficacy in patients with AML. Natural killer (NK) cells are central players in AML-targeting immune responses. However, little is known on the relationship between co-inhibitory receptors expressed by NK cells and the ability of the latter to control AML. Here, we show that hepatitis A virus cellular receptor 2 (HAVCR2, best known as TIM-3) is highly expressed by NK cells from AML patients, correlating with improved functional licensing and superior effector functions. Altogether, our data indicate that NK cell frequency as well as TIM-3 expression levels constitute prognostically relevant biomarkers of active immunity against AML.

• Keywords
• Co-inhibitory receptor, innate lymphoid cells, lag-3, tigit, vista,
• MeSH
• Leukemia, Myeloid, Acute * drug therapy   MeSH
• Hepatitis A Virus Cellular Receptor 2 * MeSH
• Killer Cells, Natural * MeSH
• CD8-Positive T-Lymphocytes MeSH
• T-Lymphocytes, Cytotoxic MeSH
• Humans MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Hepatitis A Virus Cellular Receptor 2 * MeSH
• HAVCR2 protein, human MeSH Browser