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Purpose: The recent success of anti-PD1 antibody in metastatic colorectal cancer (CRC) patients with microsatellite instability (MSI), known to be associated with an upregulated Th1/Tc1 gene signature, provides new promising therapeutic strategies. However, the partial objective response highlights a crucial need for relevant, easily evaluable, predictive biomarkers. Here we explore whether in situ assessment of Tbet+ tumor infiltrating lymphocytes (TILs) reflects a pre-existing functional antitumor Th1/Tc1/IFNγ response, in relation with clinicopathological features, microsatellite status and expression of immunoregulatory molecules (PD1, PDL1, IDO-1). Methodology: In two independent cohorts of CRC (retrospective n = 80; prospective n = 27) we assessed TILs density (CD3, Tbet, PD1) and expression profile of PDL1 and IDO-1 by immunohistochemistry/image analysis. Furthermore, the prospective cohort allowed to perform ex vivo CRC explant cultures and measure by Elisa the IFNγ response, at baseline and upon anti-PD1 treatment. Results: The density of Tbet+ TILs was significantly higher in MSI CRC, especially in the medullary subtype but also in a subgroup of MSS (microsatellite stable), and positively correlated with PD1 and PDL1 expression, but not with IDO-1. Finally, a high number of Tbet+ TILs was associated with a favorable overall survival. These Tbet+ TILs were functional as their density positively correlated with basal IFNγ levels. In addition, the combined score of Tbet+ PD1+ TILs coupled with IDO-1 expression predicted the magnitude of the IFNγ response upon anti-PD1. Conclusion: Altogether, immunohistochemical quantification of Tbet+ TILs is a reliable and accurate tool to recapitulate a preexisting Th1/Tc1/IFNγ antitumor response that can be reinvigorated by anti-PD1 treatment. [ABSTRACT FROM AUTHOR]

Immunotherapy is becoming one of today's most important systemic treatments in oncology after demonstrating its efficacy and acceptable tolerance in many types of cancer.[1] However, with increasing patient exposition, new side effects appear, including cutaneous ones. This granulomatous reaction, as triggers, could induce widespread reactions in other black tattoos, called a "rush phenomenon".[5] The granulomatous reactions related to immunotherapy, whether cutaneous or systemic, correspond to a real entity that is still poorly understood. 5 Sepehri M, Hutton Carlsen K, Serup J. Papulo-nodular reactions in black tattoos as markers of sarcoidosis: study of 92 tattoo reactions from a hospital material. [Extracted from the article]

Simple Summary: The evolution of colorectal cancer (CRC) is influenced by complex interactions between tumor cells and tumor-infiltrating lymphocytes (TILs). Optimized immunotherapies to boost the potential anti-tumor T-cell response are still needed in CRC. A good candidate is the inflammasome pathway that bridges innate and adaptive immunity via the caspase-1/interleukin-18 (IL-18) axis, able to elicit a T-helper/cytotoxic (Th1/Tc1) anti-tumor response. This study aimed to determine the status of the caspase-1/IL-18 axis in tumor cells and its potential modulatory role on TILs in CRC. Using cohorts of CRC patients and an ex vivo explant culture model allowing functional and multiparametric approaches, we demonstrate that tumor cells in the majority of CRCs can be considered as innate immune cells that display a functional caspase-1/IL-18 axis able to modulate the adaptive Th1/Tc1 anti-tumor response of TILs. Furthermore, the identification of three distinct subgroups of CRC will provide a rationale for future strategies targeting the inflammasome pathway in CRC. In colorectal cancer (CRC), a high density of T lymphocytes represents a strong prognostic marker in subtypes of CRC. Optimized immunotherapy strategies to boost this T-cell response are still needed. A good candidate is the inflammasome pathway, an emerging player in cancer immunology that bridges innate and adaptive immunity. Its effector protein caspase-1 matures IL-18 that can promote a T-helper/cytotoxic (Th1/Tc1) response. It is still unknown whether tumor cells from CRC possess a functional caspase-1/IL-18 axis that could modulate the Th1/Tc1 response. We used two independent cohorts of CRC patients to assess IL-18 and caspase-1 expression by tumor cells in relation to the density of TILs and the microsatellite status of CRC. Functional and multiparametric approaches at the protein and mRNA levels were performed on an ex vivo CRC explant culture model. We show that, in the majority of CRCs, tumor cells display an activated and functional caspase-1/IL-18 axis that contributes to drive a Th1/Tc1 response elicited by TILs expressing IL-18Rα. Furthermore, unsupervised clustering identified three clusters of CRCs according to the caspase-1/IL-18/TIL density/interferon gamma (IFNγ) axis and microsatellite status. Together, our results strongly suggest that targeting the caspase-1/IL-18 axis can improve the anti-tumor immune response in subgroups of CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma is a cancer that remains incurable. Among the many therapies under evaluation, antibodies can be used as vehicles to target and deliver toxic radiation to the tumour cells. Our objective was therefore to investigate the potential of targeted alpha therapy, combining an anti-CD138 mAb with astatine-211, to destroy the residual cells responsible for relapse. We have shown in a mouse model that mimics human disease, that destroying multiple myeloma cells is feasible with low toxicity by injecting an anti-CD138 mAb coupled with astatine-211. This approach could eradicate residual cells after initial treatment and thus prevent recurrence. Despite therapeutic progress in recent years with the introduction of targeted therapies (daratumumab, elotuzumab), multiple myeloma remains an incurable cancer. The question is therefore to investigate the potential of targeted alpha therapy, combining an anti-CD138 antibody with astatine-211, to destroy the residual cells that cause relapses. A preclinical syngeneic mouse model, consisting of IV injection of 1 million of 5T33 cells in a KaLwRij C57/BL6 mouse, was treated 10 days later with an anti-mCD138 antibody, called 9E7.4, radiolabeled with astatine-211. Four activities of the 211At-9E7.4 radioimmunoconjugate were tested in two independent experiments: 370 kBq (n = 16), 555 kBq (n = 10), 740 kBq (n = 17) and 1100 kBq (n = 6). An isotype control was also tested at 555 kBq (n = 10). Biodistribution, survival rate, hematological parameters, enzymatic hepatic toxicity, histological examination and organ dosimetry were considered. The survival median of untreated mice was 45 days after engraftment. While the activity of 1100 kBq was highly toxic, the activity of 740 kBq offered the best efficacy with 65% of overall survival 150 days after the treatment with no evident sign of toxicity. This work demonstrates the pertinence of treating minimal residual disease of multiple myeloma with an anti-CD138 antibody coupled to astatine-211. [ABSTRACT FROM AUTHOR]