Breast Cancer Neoantigens Can Induce CD8+ T-Cell Responses and Antitumor Immunity

Zhang, Xiuli; Kim, Samuel; Hundal, Jasreet; Herndon, John M.; Li, Shunqiang; Petti, Allegra A.; Soysal, Savas D.; Li, Lijin; McLellan, Michael D.; Hoog, Jeremy; Primeau, Tina; Myers, Nancy B.; Vickery, Tammi L.; Sturmoski, Mark; Hagemann, Ian S.; Miller, Christopher A.; Ellis, Matthew J.; Mardis, Elaine R.; Hansen, Ted H.; Fleming, Timothy P.; Goedegebuure, Peter S.; Gillanders, William E.

doi:10.1158/2326-6066.cir-16-0264

Cited by 72 publications

(57 citation statements)

References 43 publications

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“…In fact, both the burden of tumor mutations and the load of neo-epitopes represent two of the factors that are linked to response to checkpoint inhibitors in different malignancies like melanoma or lung cancer [63]. However, although tumor neoantigens that are produced as a result of breast cancer cells' genomic instability can be recognized by the immune system and induce T-cell responses and antitumor immunity [62,64], the immunogenicity of breast cancer can be rather heterogeneous, depending to a large extent on the specific subtype of breast cancer [65].…”

Section: Breast Tumor Microenvironmentmentioning

confidence: 99%

Immunotherapy: A Challenge of Breast Cancer Treatment

García-Aranda

Redondo

2019

Cancers

140

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Breast cancer is the most commonly diagnosed cancer in women and is a leading cause of cancer death in women worldwide. Despite the significant benefit of the use of conventional chemotherapy and monoclonal antibodies in the prognosis of breast cancer patients and although the recent approval of the anti-PD-L1 antibody atezolizumab in combination with chemotherapy has been a milestone for the treatment of patients with metastatic triple-negative breast cancer, immunologic treatment of breast tumors remains a great challenge. In this review, we summarize current breast cancer classification and standard of care, the main obstacles that hinder the success of immunotherapies in breast cancer patients, as well as different approaches that could be useful to enhance the response of breast tumors to immunotherapies.

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Section: Breast Tumor Microenvironmentmentioning

confidence: 99%

Immunotherapy: A Challenge of Breast Cancer Treatment

García-Aranda

Redondo

2019

Cancers

140

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“…Furthermore, immunocompetent cells are able to recognize TSAs/ neoepitopes as being foreign [27]. It was shown that TILs, especially cytotoxic T cells, recognize TSAs/neoepitopes in breast cancer and are able to induce antitumor responses in mice [28]. However, the knowledge about somatic mutations causing tumor regression is limited [29] and might be unique for each patient.…”

Section: Introductionmentioning

confidence: 99%

TILGen: A Program to Investigate Immune Targets in Breast Cancer Patients - First Results on the Influence of Tumor-Infiltrating Lymphocytes

et al. 2018

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Background: Despite advancements in the treatment of primary and metastatic breast cancer, many patients lack a durable response to these treatments. Patients with triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2(HER2)-positive breast cancer who do not have a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) have a very poor prognosis. Tumor-infiltrating lymphocytes (TILs) have been identified as a predictive marker for pCR after NACT in TNBC and HER2-positive breast cancer. These patient populations could also be suitable for novel treatment strategies including neoepitope-based therapies. This work analyses the effect of TILs on the pCR in neoadjuvantly treated patients in the TILGen study and presents the procedures aimed at establishing neoepitope-based therapies in this study. Methods: Neoadjuvantly treated HER2-positive and TNBC patients were eligible for the presented analysis concerning the association between TILs and pCR. A total of 146 patients could be identified within the TILGen study. TILs were evaluated as percentage of stromal tumor tissue in core biopsies at primary diagnosis. The phenotype ‘lymphocyte-predominant breast cancer' (LPBC) was associated with pCR by logistic regression adjusted for estrogen receptor status, progesterone receptor status, HER2 status, age at diagnosis, and grading. Results: LPBC was seen in 24 (16.4%) patients. In this patient group, 66.7% achieved a pCR, while the pCR rate was 32.8% in patients with a low TIL count. The adjusted odds ratio was 6.60 (95% confidence interval 2.02-21.56; p < 0.01). Conclusion: TILs are a strong predictor of pCR in TNBC and HER2-positive breast cancer patients. Implications for the use of this information including the effect on prognosis might help to identify patients most likely to benefit from a neoepitope-based therapy approach.

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“…In a small group of patients with stages III and IV melanoma, Ott et al demonstrated only 16% neoantigens, which were predicted by NetMHCpan-2.4 algorithm, were recognized by CD8 + T cell [37]. Zhang et al found a significant T-cell response in two of nine neoantigens for one breast cancer patient, and one of eight neoantigens for the other two patients with breast cancer, in which neoantigens were predicted by NetMHC-3.2 algorithm [38]. Therefore, we considered that none of the current algorithms was perfect, and it was necessary to simultaneously use multiple algorithms to increase the accuracy of peptide binding affinity prediction.…”

Section: Discussionmentioning

confidence: 99%

The common neoantigens in colorectal cancer are predicted and validated to be presented or immunogenic

Liang

Qin

et al. 2019

Preprint

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23Colorectal cancer (CRC) is a malignant cancer with high incidence and mortality in the 24 world, as the result of the traditional treatments. Immunotherapy targeting neoantigens 25 can induce durable tumor regression in cancer patients, but is almost limited to 26 individual treatment, resulting from the unique neoantigens. Many shared oncogenic 27 mutations are detected, but whether the common neoantigens can be identified in CRC 28 is unknown. Using the somatic mutations data from 321 CRC patients combined with 29 a filter standard and 7 predicted algorithms, we screened and obtained 25 HLA-30 A*11:01 restricted common neoantigens with high binding affinity (IC50<50 nM) and 31 presentation score (EPIC>0.9). Except the positive epitope KRAS_G12V8-16, 11 out of 32 25 common neoantigens were proved to be naturally processed and presented on 33 constructed K562 cell surface by mass spectroscopy (MS), and 11 out of 25 common 34 neoantigens specifically induced in vitro pre-stimulated cytotoxic lymphocyte (CTL) 35 to secrete IFN-. However, only 2 out of 25 common neoantigens were simultaneously 36 presented and immunogenic. Moreover, using cell-sorting technology combined with 37 single-cell RNA sequencing, the immune repertoire profiles of C1orf170_S418G413-421 38 and KRAS_G12V8-16-specific CTL were clarified. Therefore, common neoantigens 39 with presentation and immunogenicity could be found in CRC, which would be 40 developed as the universal targets for CRC immunotherapy. 41 42 43 44 45 46 Colorectal cancer (CRC) is the third commonest diagnosed malignant cancer and 47 the second leading cause of cancer death in the world [1]. In 2018, more than 1.8 48 million new cases of CRC and almost 881 thousand cases of CRC-interrelated death 49 occurred in the world [1], and the global burden of CRC is estimated to reach over 2.2 50 million new cases and 1.1 million cancer deaths by 2030 [2]. Traditionally surgical 51 resection can cure the early stage of CRC, but about 50% of patients ultimately die of 52 distant metastases. While chemotherapy, radiation therapy and targeted therapy can 53 extend overall survival, less than 15% of patients with metastatic CRC survive 54 beyond 5 years [3]. Therefore, the novel and more effective therapeutic approaches 55 for CRC are necessary to develop. 56 In the recent years, based on a better knowledge of the complex interactions 57 between the immune system and the tumor microenvironment, immunotherapy has 58 become a novel effective and promising therapeutic strategy for cancer, and its 59 efficacy was widely tested by CRC model. The vast majority of CRC patients with 60 deficient mismatch repair (dMMR) or highly microsatellite instable (MSI-H) benefit 61 from immune checkpoint inhibitors, which is not effective in other CRC patients with 62 proficient MMR (pMMR) or microsatellite stable (MSS) [4]. Patients with CRC do 63 not respond to autologous tumour lysate DC (ADC) and peptide vaccines [4]. T cells, 64 which are engineered to express an affinity-enhanced T-cell rece...

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Breast Cancer Neoantigens Can Induce CD8+ T-Cell Responses and Antitumor Immunity

Cited by 72 publications

References 43 publications

Immunotherapy: A Challenge of Breast Cancer Treatment

Immunotherapy: A Challenge of Breast Cancer Treatment

TILGen: A Program to Investigate Immune Targets in Breast Cancer Patients - First Results on the Influence of Tumor-Infiltrating Lymphocytes

The common neoantigens in colorectal cancer are predicted and validated to be presented or immunogenic

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