Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade

Chen, Pei-Ling; Roh, Whijae; Reuben, Alexandre; Cooper, Zachary A.; Spencer, Christine N.; Prieto, Peter A.; Miller, John P.; Bassett, Roland L.; Gopalakrishnan, Vancheswaran; Wani, Khalida; Macedo, Mariana Petaccia de; Austin-Breneman, Jacob L.; Jiang, Hong; Chang, Qing; Reddy, Sangeetha M.; Chen, Wei Shen; Tetzlaff, Michael T.; Broaddus, Russell; Gershenwald, Jeffrey E.; Haydu, Lauren E.; Lazar, Alexander J.; Patel, Sapna; Hwu, Patrick; Hwu, Wen Jen; Diab, Adi; Glitza, Isabella C.; Woodman, Scott E.; Vence, Luis M.; Wistuba, Ignacio I.; Amaria, Rodabe N.; Kwong, Lawrence N.; Prieto, Víctor G.; Davis, R. Eric; Ma, Wencai; Overwijk, Willem W.; Sharpe, Arlene H.; Hu, Jianhua; Futreal, P. Andrew; Blando, Jorge; Sharma, Padmanee; Allison, James P.; Chin, Lynda; Wargo, Jennifer A.

doi:10.1158/2159-8290.cd-15-1545

Cited by 824 publications

(778 citation statements)

References 46 publications

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“…Some tumors with low TMB respond completely. Response to immunotherapy has also been associated with intratumoral gene-based markers of T cell activation and antigen presentation 33,34 but such markers have not been introduced to practice. Triple negative breast cancer (TNBC), which comprises the majority of Basal-like tumors, is characterized by relatively high TMB.…”

Section: Discussionmentioning

confidence: 99%

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%

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

et al. 2018

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“…In addition to genomic-based biomarkers, immune signatures of response to PD1/PD-L1 inhibition have been recently proposed [25,31]. In particular, a six IFN-γ-related genes signature of response to pembrozulimab has been established in metastatic HNSCC [14].…”

Section: Discussionmentioning

confidence: 99%

The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade

et al. 2017

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To cite this version:P. Foy, Chloé Bertolus, Marie-Cécile Michallet, Sophie Deneuve, R. Incitti, et al.. The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade. Annals of Oncology, Oxford University Press (OUP), 2017, 28 (8), pp.1934-1941 Background: Never-smokers and never-drinkers patients (NSND) suffering from oral

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“…Several studies show that some markers offer better predictive information when the biopsy is performed after treatment initiation (9,36,43 Although gene signatures can become easily available for clinical practice, they need validation in the context of immunotherapy. mRNA concentration of PD-L1 and other key regulator molecules are subjected to post-transcriptional regulation, so gene signatures might not properly detect them.…”

Section: Gene Signaturesmentioning

confidence: 99%

Predictive factors of response to immunotherapy—a review from the Spanish Melanoma Group (GEM)

et al. 2017

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Immunotherapy has become a key element in the treatment of several tumors, such as lung carcinoma and melanoma. Immunotherapy, unlike classical chemotherapy and targeted drugs, may yield long-term survival, even in patients who stop treatment due to toxicity. This fact has generated considerable excitement and a real shift in the paradigm of cancer treatment. However, only a small subset of patients benefit from immunotherapy. Survival curves show that most patients have progression of the disease in the first months after starting immunotherapy, followed by a slower decrease over the first 3 years, until curves reach a plateau. This early progression suggests the presence of mechanisms for primary resistance.In addition, some patients have tumor relapse after years of response, suggesting that there is also acquired resistance in a small subset of patients. Resistance mechanisms are now being elucidated. PD-L1 expression in tumor and immune cells correlates with higher chances of response, but melanoma patients with PD-L1 negative tumors can also respond. Several studies have demonstrated an increased probability of clinical benefit when tumors are infiltrated by CD8 T cells, have a high mutation burden or have an interferon gamma signature. But none of these factors has been implemented in the clinical practice, since more studies confirming their value are needed, as well as the development of standardized techniques.

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Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade

Cited by 824 publications

References 46 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

The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade

Predictive factors of response to immunotherapy—a review from the Spanish Melanoma Group (GEM)

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