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The multicenter international Society for Immunotherapy of Cancer (SITC) study of the consensus Immunoscore demonstrated the prediction of survival and response to chemotherapy in 763 Stage III colon cancer (CC) patients. Similar Immunoscore groups were found in elderly patients, and densities of immune cells and intratumoral T-cell repertoire were not decreasing with age in the tumor microenvironment. In two independent cohorts, Immunoscore significantly predicted time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS), including within high-risk (T4 or N2) and low-risk (T1-3, N1) patients. In stratified Cox multivariable analysis for TTR, DFS, and OS, Immunoscore's association to outcomes was independent of the patient's age, sidedness, gender, T-stage, N-stage, and microsatellite instability status. Furthermore, the relative contribution to the risk test showed that Immunoscore had the highest contribution to survival. Importantly Immunoscore predicted the likelihood of response to chemotherapy. Only patients with a high-Immunoscore significantly benefited from chemotherapy. The prognostic value of Immunoscore was confirmed in two independent phase 3 clinical trials (NCCTG-N0147, n = 559; Prodige-IDEA, n = 1062). Moreover, results from IDEA phase 3 randomized trial revealed the predictive value of Immunoscore for response to adjuvant FOLFOX chemotherapy duration. The latest edition of the WHO Digestive System Tumors classification introduced the immune response as measured by Immunoscore as essential and desirable diagnostic criteria for CC, and Immunoscore was introduced into the 2020 ESMO Clinical Practice Guidelines for CC to refine the prognosis and adjust chemotherapy decision-making process in stages II and III patients. These results highlight the clinical utility of Immunoscore. [ABSTRACT FROM AUTHOR]

A cancer immune signature implicating good prognosis and responsiveness to immunotherapy was described that is observed also in other aspects of immune-mediated, tissue-specific destruction (TSD). Its determinism remains, however, elusive. Based on limited but unique clinical observations, we propose a multifactorial genetic model of human cancer immune responsiveness. [ABSTRACT FROM AUTHOR]

The authors reflect on the meta-analysis and metagenes regarding the use of CXCL-13 gene as a marker of intratumoral immune response and predictor for chemotherapeutic outcome of breast cancer. Topics include the cancer immunotherapy, response to neoadjuvant chemotherapy, and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) monoclonal antibody (mAb).

The introduction of immune checkpoint blockade into the clinical practice resulted in improvement of survival of a significant portion of melanoma patients. Consequently, predictive biomarkers of response are needed to optimize patient's stratification and the development of combination therapies. The aim of this study was to determine whether levels of soluble NKG2D ligands (MICA, MICB, ULBP1, 2 and 3; sNKG2DLs) in the serum of melanoma patients can serve as useful predictors of response to the treatment with immune checkpoint blockade. sNKG2DLs were measured by ELISA in baseline and post-treatment serum and these results were correlated with the clinical outcome of melanoma patients (N= 194). The same determinations were performed also in a cohort of patients (N= 65) treated with either chemotherapy, radiotherapy, or mutated BRAF inhibitors (BRAFi). Absence of soluble MICB and ULBP-1 in baseline serum correlated with improved survival (OS = 21.6 and 25.3 mo andp= 0.02 and 0.01, respectively) of patients treated with immunological therapies while detectable levels of these molecules were found in poor survivors (OS = 8.8 and 12.1 mo, respectively). Multivariate analysis showed that LDH (p<0.0001), sULBP-1 (p= 0.02), and sULBP-2 (p= 0.02) were independent predictors of clinical outcome for the cohort of melanoma patients treated with immune checkpoint blockade. Only LDH but not sNKG2DLs was significantly associated with the clinical outcome of patients treated with standard or BRAFi regimens. These findings highlight the relevance of sNKG2DLs in the serum of melanoma patients as biomarkers for patients' stratification and optimization of immune checkpoint inhibition regimens. [ABSTRACT FROM PUBLISHER]

Cancer immunotherapy is revolutionizing the clinical management of several tumors, but has demonstrated limited activity in breast cancer. The development of more effective treatments is hindered by incomplete knowledge of the genetic determinant of immune responsiveness. To fill this gap, we mined copy number alteration, somatic mutation, and expression data from The Cancer Genome Atlas (TCGA). By using RNA-sequencing data from 1,004 breast cancers, we defined distinct immune phenotypes characterized by progressive expression of transcripts previously associated with immune-mediated rejection. The T helper 1 (Th-1) phenotype (ICR4), which also displays upregulation of immune-regulatory transcripts such asPDL1, PD1, FOXP3, IDO1, andCTLA4, was associated with prolonged patients' survival. We validated these findings in an independent meta-cohort of 1,954 breast cancer gene expression data. Chromosome segment 4q21, which includes genes encoding for the Th-1 chemokines CXCL9-11, was significantly amplified only in the immune favorable phenotype (ICR4). The mutation and neoantigen load progressively decreased from ICR4 to ICR1 but could not fully explain immune phenotypic differences. Mutations ofTP53were enriched in the immune favorable phenotype (ICR4). Conversely, the presence ofMAP3K1andMAP2K4mutations were tightly associated with an immune-unfavorable phenotype (ICR1). Using both the TCGA and the validation dataset, the degree of MAPK deregulation segregates breast tumors according to their immune disposition. These findings suggest that mutation-driven perturbations of MAPK pathways are linked to the negative regulation of intratumoral immune response in breast cancer. Modulations of MAPK pathways could be experimentally tested to enhance breast cancer immune sensitivity. [ABSTRACT FROM AUTHOR]

We have identified eight genes whose expression in human melanoma metastases and ovarian cancers is associated with a lack of Th1 immune signatures. They encode molecules with mechanical barrier function in the skin and other normal tissues and include filaggrin (FLG), tumor-associated calcium signal transducer 2 (TACSTD2), and six desmosomal proteins (DST, DSC3, DSP, PPL, PKP3, and JUP). This association has been validated in an independent series of 114 melanoma metastases. In these, DST expression alone is sufficient to identify melanomas without immune signatures, while FLG and the other six putative barrier molecules are overexpressed in a different subset of melanomas lacking immune signatures. Similar associations have been identified in a set of 186 ovarian cancers. RNA-seq data from 471 melanomas and 307 ovarian cancers in the TCGA database further support these findings and also reveal that overexpression of barrier molecules is strongly associated with early patient mortality for melanoma (p= 0.0002) and for ovarian cancer (p< 0.01). Interestingly, this association persists for FLG for melanoma (p= 0.012) and ovarian cancer (p= 0.006), whereas DST overexpression is negatively associated with CD8+gene expression, but not with patient survival. Thus, overexpression of FLG or DST identifies two distinct patient populations with low immune cell infiltration in these cancers, but with different prognostic implications for each. These data raise the possibility that molecules with mechanical barrier function in skin and other tissues may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction. [ABSTRACT FROM AUTHOR]

In a recent adoptive cell therapy (ACT) clinical trial using autologous tumor-infiltrating lymphocytes (TILs) in patients with metastatic melanoma, we found an association between CD8+T cells expressing the inhibitory receptor B- and T-lymphocyte attenuator (BTLA) and clinical response. Here, we further characterized this CD8+BTLA+TIL subset and their CD8+BTLA−counterparts. We found that the CD8+BTLA+TILs had an increased response to IL-2, were less-differentiated effector-memory (TEM) cells, and persisted longerin vivoafter infusion. In contrast, CD8+BTLA−TILs failed to proliferate and expressed genes associated with T-cell deletion/tolerance. Paradoxically, activation of BTLA signaling by its ligand, herpes virus entry mediator (HVEM), inhibited T-cell division and cytokine production, but also activated the Akt/PKB pathway thus protecting CD8+BTLA+TILs from apoptosis. Our results point to a new role of BTLA as a useful T-cell differentiation marker in ACT and a dual signaling molecule that curtails T-cell activation while also conferring a survival advantage for CD8+T cells. These attributes may explain our previous observation that BTLA expression on CD8+TILs correlates with clinical response to adoptive T-cell therapy in metastatic melanoma. [ABSTRACT FROM PUBLISHER]