Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

McGranahan, Nicholas; Furness, Andrew J.S.; Rosenthal, Rachel; Ramskov, Sofie; Lyngaa, Rikke; Saini, Sunil Kumar; Jamal‐Hanjani, Mariam; Wilson, Gareth A.; Birkbak, Nicolai J.; Hiley, Crispin; Watkins, Thomas B.K.; Shafi, Seema; Murugaesu, Nirupa; Mitter, Richard; Akarca, Ayse U.; Linares, Josep; Marafioti, Teresa; Henry, Jake Y.; Allen, Eliezer M. Van; Miao, Diana; Schilling, Bastian; Schadendorf, Dirk; Garraway, Levi A.; Makarov, Vladimir; Rizvi, Naiyer A.; Snyder, Alexandra; Hellmann, Matthew D.; Merghoub, Taha; Wolchok, Jedd D.; Shukla, Sachet A.; Wu, Catherine J.; Peggs, Karl S.; Chan, Timothy A.; Hadrup, Sine Reker; Quezada, Sergio A.; Swanton, Charles

doi:10.1126/science.aaf1490

Cited by 2,619 publications

(2,400 citation statements)

References 36 publications

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“…9,10,30–32 Although associated with efficacy, TMB has not yet been deemed sufficiently predictive to be of clinical use. Many tumors with high TMB are not responsive to immune checkpoint inhibitors.…”

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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“…While being an adverse prognostic marker, a nonsynonymous NF1 mutation can be a favorable treatment‐predictive marker, by virtue of its association with increased mutational load. In particular, tumors with high mutational burden (or deficiency in the DNA mismatch repair pathway leading to such an increase) have recently been shown to respond better to immune checkpoint blockade agents (Le et al ., 2015; McGranahan et al ., 2016; Rizvi et al ., 2015; Van Allen et al ., 2015). Furthermore, NF1 ‐mutant melanomas have been found to be dependent on MAPK signaling and to respond to inhibitors targeting key players of this pathway (MEK, ERK) (Maertens et al ., 2013; Nissan et al ., 2014; Whittaker et al ., 2013).…”

Section: Discussionmentioning

confidence: 99%

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

et al. 2017

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In general, melanoma can be considered as a UV‐driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen‐activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF,RAS,NF1 mutation or triple‐wild‐type status and correlated with tumor and patient characteristics. We found that the NF1‐mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co‐occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain‐containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1‐mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease‐specific survival, DSS; HR, 1.9; 95% CI, 1.21–3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28–2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.

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“…19 Subsequently, the IFN-γ produced by recruited stimulated lymphocytes, which has been described to be crucial for Th1 immunity and trastuzumab response, 26 would in turn induce CXCLs in tumor cells followed by improved T cell-trafficking and maintenance of immune-enriched TME. Although tumor antigenicity derived from a high mutational burden, as demonstrated in patients with melanoma and lung cancer who respond to immune-checkpoint inhibitors, 27-29 may also explain the infiltration of HER2+ BCs by adaptive immune cells, the low mutational burden of BCs compared to melanoma 30 and the lack of association between the amount of neoantigens and TIL count or trastuzumab activity in tumors from patients enrolled in the FinHer trial 31 do not support this possibility. Considering that CXCLs and HER2 mRNA levels are significantly positively correlated in HER2+ BC samples and in our in vitro models, it could be hypothesized that these molecules are co-regulated in trastuzumab responsive HER2-addicted tumors, the subgroup with the highest HER2 transcription.…”

Section: Discussionmentioning

confidence: 99%

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

et al. 2018

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Through whole-transcriptome profiling of HER2+ breast carcinomas (BCs), we previously showed that those sensitive to trastuzumab are addicted to this oncoprotein and are enriched in immune pathways, raising the hypothesis that HER2 itself regulates immune cell recruitment. In the present study we investigated the relationship between HER2 activity and the pro-trastuzumab tumor immune milieu. Gene expression profiling and immunohistochemistry analysis of 53 HER2+ BCs showed that trastuzumab-sensitive tumors expressed significantly higher levels of chemokines involved in immune cell recruitment, with higher infiltration of T cells and monocytes, and higher levels of PD-1 ligands than tumors that do not benefit from trastuzumab. In vitro analysis in HER2+ BC cells revealed that CCL2 production was induced by HER2 stimulation with EGF/HRG via the PI3K-NF-kB axis, and down-modulated by HER2 inhibition with trastuzumab. CCL2 expression was higher in HER2+/ER− than HER2+/ER+ BC cell lines, and degradation of ER by fulvestrant induced an enhancement in NF-κB transcriptional activity and consequent CCL2 expression. Trastuzumab efficacy relied on CCL2 levels and monocytes present in the tumor microenvironment in FVB mice bearing HER2+ mammary carcinoma cells. HER2 signals were also found to sustain the expression of PD-1 ligands in tumor cells via the MEK pathway.Overall, our results support the concept that the activated HER2 oncogene regulates recruitment and activation of tumor infiltrating immune cells and trastuzumab activity by inducing CCL2 and PD-1 ligands and that ER activity negatively controls the HER2-driven pro-trastuzumab tumor microenvironment.

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Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

Cited by 2,619 publications

References 36 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

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

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