Molecular and Genetic Properties of Tumors Associated with Local Immune Cytolytic Activity

Rooney, Michael S.; Shukla, Sachet A.; Wu, Catherine J.; Getz, Gad; Hacohen, Nir

doi:10.1016/j.cell.2014.12.033

Cited by 3,120 publications

(3,503 citation statements)

References 77 publications

(70 reference statements)

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“…Patients with TMB-Lo FID tumors, in contrast to those with TMB-Hi FID, did not experience a protective survival benefit as compared to WID and PID, suggesting a tolerant or tumor-promoting immune infiltrate that may facilitate immune evasion. 26 PID tumors, characterized by low level effector cell infiltrates, comprised the largest immune subclass (49% of tumors). This subclass comprised 44% of the TMB-Hi group where it was associated with worse survival consistent with a poor tumor-mediated immune response, despite high TMB.…”

Section: Discussionmentioning

confidence: 99%

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Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

et al. 2018

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Mounting evidence supports a role for the immune system in breast cancer outcomes. The ability to distinguish highly immunogenic tumors susceptible to anti-tumor immunity from weakly immunogenic or inherently immune-resistant tumors would guide development of therapeutic strategies in breast cancer. Genomic, transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were used to examine statistical associations between tumor mutational burden (TMB) and the survival of patients whose tumors were assigned to previously-described prognostic immune subclasses reflecting favorable, weak or poor immune-infiltrate dispositions (FID, WID or PID, respectively). Tumor immune subclasses were associated with survival in patients with high TMB (TMB-Hi, P < 0.001) but not in those with low TMB (TMB-Lo, P = 0.44). This statistical relationship was confirmed in the METABRIC cohort (TMB-Hi, P = 0.047; TMB-Lo, P = 0.39), and also found to hold true in the more-indolent Luminal A tumor subtype (TMB-Hi, P = 0.011; TMB-Lo, P = 0.91). In TMB-Hi tumors, the FID subclass was associated with prolonged survival independent of tumor stage, molecular subtype, age and treatment. Copy number analysis revealed the reproducible, preferential amplification of chromosome 1q immune-regulatory genes in the PID immune subclass. These findings demonstrate a previously unappreciated role for TMB as a determinant of immune-mediated survival of breast cancer patients and identify candidate immune-regulatory mechanisms associated with immunologically cold tumors. Immune subtyping of breast cancers may offer opportunities for therapeutic stratification.

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Section: Discussionmentioning

confidence: 99%

“…In other solid cancers, TMB as a reflection of neoantigen load is associated with cytolytic activity 26 and efficacy of immune therapies. 9,10,30–32 Although associated with efficacy, TMB has not yet been deemed sufficiently predictive to be of clinical use.…”

Section: Discussionmentioning

confidence: 99%

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

et al. 2018

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“…Because CITA/NLRC5-mediated MHC class I expression is crucial for optimal activation and cytolytic activity of CD8 + T cells (18,19), we next examined the expression level of perforin (PRF1) or granzyme A (GZMA), which are known to be associated with cytotoxic T-cell activity in cancer tissues (23). Indeed, the cohort of 16 solid cancer etiologies revealed a significant positive correlation between NLRC5 expression and PRF1 or GZMA (Fig.…”

Section: Significancementioning

confidence: 99%

NLRC5/MHC class I transactivator is a target for immune evasion in cancer

Yoshihama

Roszik

Downs

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

226

242

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Cancer cells develop under immune surveillance, thus necessitating immune escape for successful growth. Loss of MHC class I expression provides a key immune evasion strategy in many cancers, although the molecular mechanisms remain elusive. MHC class I transactivator (CITA), known as "NLRC5" [NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5], has recently been identified as a critical transcriptional coactivator of MHC class I gene expression. Here we show that the MHC class I transactivation pathway mediated by CITA/NLRC5 constitutes a target for cancer immune evasion. In all the 21 tumor types we examined, NLRC5 expression was highly correlated with the expression of MHC class I, with cytotoxic T-cell markers, and with genes in the MHC class I antigen-presentation pathway, including LMP2/LMP7, TAP1, and β2-microglobulin. Epigenetic and genetic alterations in cancers, including promoter methylation, copy number loss, and somatic mutations, were most prevalent in NLRC5 among all MHC class I-related genes and were associated with the impaired expression of components of the MHC class I pathway. Strikingly, NLRC5 expression was significantly associated with the activation of CD8 + cytotoxic T cells and patient survival in multiple cancer types. Thus, NLRC5 constitutes a novel prognostic biomarker and potential therapeutic target of cancers.MHC class I | CITA | cancer | immune evasion | NLRC5

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“…For the poor-prognosis basal-like, non-immune infiltrated tumors, inducing lymphocyte infiltration in immune 'quiet' tumors poses a greater challenge than activating lymphocytes in tumors with existing TILs. Although tumor immunogenicity is hypothesized to relate to the number of 'neoantigens,' or tumor-specific antigens recognized as foreign, and neoantigen load has been associated with response to immune checkpoint therapies [63,64], breast cancers have relatively few somatic mutations and inferred neoantigen load [65]. Analyses to date do not show a positive correlation between mutational or neoantigen load and gene expression evidence of immune cell infiltration in TNBCs [66].…”

Section: Enhancing Breast Cancer Immunogenicitymentioning

confidence: 99%

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

Telli

Stover

Loi

et al. 2018

Breast Cancer Res Treat

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Purpose Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit. Methods We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection. Results Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise. Conclusions HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of 'immune cold' TNBCs.

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Molecular and Genetic Properties of Tumors Associated with Local Immune Cytolytic Activity

Cited by 3,120 publications

References 77 publications

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

NLRC5/MHC class I transactivator is a target for immune evasion in cancer

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

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