Purpose: The association of human leucocyte antigen (HLA) class I expression levels with the clinical course of many malignancies reflects their crucial role in the recognition and elimination of... Show morePurpose: The association of human leucocyte antigen (HLA) class I expression levels with the clinical course of many malignancies reflects their crucial role in the recognition and elimination of malignant cells by cognate T cells and NK cells. In colorectal cancer, results regarding this association are conflicting. The potential pathogenetic and therapeutic implications of this association prompted us to perform a large patient-level pooled analysis assessing the role of the expression level of HLA class I loci gene products in colon and rectal cancer. Experimental design: Included studies provided patient-level data on HLA class I expression levels determined by immunohistochemistry on surgical specimens. Expression levels of the HLA class I loci gene products (HLA-A, HLA-B/C) were correlated with common genetic events and survival. Results: Data from 5 studies including 2863 patients were used. In the 1620 colon cancer patients, lower HLA-A, HLA-B/C and total HLA class I expression levels were associated with microsatellite instability (p=0.044, p=0.008 and p=0.022, respectively), higher frequency of BRAF mutations (p<0.001, p=0.021 and p<0.001, respectively) and lower frequency of KRAS mutations (p=0.001, ns and p=0.002, respectively). In the 1243 rectal cancer patients, HLA-A expression was higher in tumors treated with neoadjuvant radiation (p=0.024). High HLA-B/C, but not HLA-A, expression level was an independent predictor of favorable overall survival in colon (p=0.006) and rectal (p<0.001) cancer. Conclusions: T-cells and HLA-B/C antigens, rather than NK cells and HLA-A antigens, likely play an important role in controlling colon/rectal cancer growth. Colon/rectal cancer patients may benefit from strategies that upregulate HLA-B/C and trigger or enhance T cell immunity. Show less
Background T cell receptor (TCR)-engineered cells can be powerful tools in the treatment of malignancies. However, tumor resistance by Human Leukocyte antigen (HLA) class I downregulation can... Show moreBackground T cell receptor (TCR)-engineered cells can be powerful tools in the treatment of malignancies. However, tumor resistance by Human Leukocyte antigen (HLA) class I downregulation can negatively impact the success of any TCR-mediated cell therapy. Allogeneic natural killer (NK) cells have demonstrated efficacy and safety against malignancies without inducing graft-versus-host-disease, highlighting the feasibility for an 'off the shelf' cellular therapeutic. Furthermore, primary NK cells can target tumors using a broad array of intrinsic activation mechanisms. In this study, we combined the antitumor effector functions of NK cells with TCR engineering (NK-TCR), creating a novel therapeutic strategy to avoid TCR-associated immune resistance. Methods BOB1, is a transcription factor highly expressed in all healthy and malignant B cell lineages, including multiple myeloma (MM). Expression of an HLA-B*07:02 restricted BOB1-specifc TCR in peripheral blood-derived NK cells was achieved following a two-step retroviral transduction protocol. NK-TCR was then compared with TCR-negative NK cells and CD8-T cells expressing the same TCR for effector function against HLA-B*07:02+ B-cell derived lymphoblastoid cell lines (B-LCL), B-cell acute lymphoblastic leukemia and MM cell lines in vitro and in vivo. Results Firstly, TCR could be reproducibly expressed in NK cells isolated from the peripheral blood of multiple healthy donors generating pure NK-TCR cell products. Secondly, NK-TCR demonstrated antigen-specific effector functions against malignancies which were previously resistant to NK-mediated lysis and enhanced NK efficacy in vivo using a preclinical xenograft model of MM. Moreover, antigen-specific cytotoxicity and cytokine production of NK-TCR was comparable to CD8 T cells expressing the same TCR. Finally, in a model of HLA-class I loss, tumor cells with B2M KO were lysed by NK-TCR in an NK-mediated manner but were resistant to T-cell based killing. Conclusion NK-TCR cell therapy enhances NK cell efficacy against tumors through additional TCR-mediated lysis. Furthermore, the dual efficacy of NK-TCR permits the specific targeting of tumors and the associated TCR-associated immune resistance, making NK-TCR a unique cellular therapeutic. Show less
Roelands, J.; Hendrickx, W.; Zoppoli, G.; Mall, R.; Saad, M.; Halliwill, K.; ... ; Bedognetti, D. 2020
BackgroundAn immune active cancer phenotype typified by a T helper 1 (Th-1) immune response has been associated with increased responsiveness to immunotherapy and favorable prognosis in some but... Show moreBackgroundAn immune active cancer phenotype typified by a T helper 1 (Th-1) immune response has been associated with increased responsiveness to immunotherapy and favorable prognosis in some but not all cancer types. The reason of this differential prognostic connotation remains unknown.MethodsTo explore the contextual prognostic value of cancer immune phenotypes, we applied a multimodal pan-cancer analysis among 31 different histologies (9282 patients), encompassing immune and oncogenic transcriptomic analysis, mutational and neoantigen load and copy number variations.ResultsWe demonstrated that the favorable prognostic connotation conferred by the presence of a Th-1 immune response was abolished in tumors displaying specific tumor-cell intrinsic attributes such as high transforming growth factor-beta (TGF-beta) signaling and low proliferation capacity. This observation was independent of mutation rate. We validated this observation in the context of immune checkpoint inhibition. WNT-beta catenin, barrier molecules, Notch, hedgehog, mismatch repair, telomerase activity and AMPK signaling were the pathways most coherently associated with an immune silent phenotype together with mutations of driver genes including IDH1/2, FOXA2, HDAC3, PSIP1, MAP3K1, KRAS, NRAS, EGFR, FGFR3, WNT5A and IRF7.ConclusionsThis is the first systematic study demonstrating that the prognostic and predictive role of a bona fide favorable intratumoral immune response is dependent on the disposition of specific oncogenic pathways. This information could be used to refine stratification algorithms and prioritize hierarchically relevant targets for combination therapies. Show less
