Low Tumor-infiltrating Lymphocytes Level Research Articles

High Probability of Lynch Syndrome Among Colorectal Cancer Patients Is Associated With Higher Occurrence of KRAS and PIK3CA Mutations.

In Indonesia, early-onset colorectal cancer (EOCRC) rates are higher in patients < 50 years old compared to Western populations, possibly due to a higher frequency of Lynch syndrome (LS) in CRC patients. We aimed to examine the association of KRAS and PIK3CA mutations with LS. In this retrospective cross-sectional single-center study, the PCR-HRM-based test was used for screening of microsatellite instability (MSI) mononucleotide markers (BAT25, BAT26, BCAT25, MYB, EWSR1), MLH1 promoter methylation, and oncogene mutations of BRAF (V600E), KRAS (exon 2 and 3), and PIK3CA (exon 9 and 20) in FFPE DNA samples. All the samples (n = 244) were from Dr. Sardjito General Hospital Yogyakarta, Indonesia. KRAS and PIK3CA mutations were found in 151/244 (61.88%) and 107/244 (43.85%) of samples, respectively. KRAS and PIK3CA mutations were significantly associated with MSI status in 32/42 (76.19%) and 25/42 (59.52%) of samples, respectively. KRAS mutation was significantly associated with LS status in 26/32 (81.25%) of samples. The PIK3CA mutation was present in a higher proportion in LS samples of 19/32 (59.38%), but not statistically significant. Clinicopathology showed that KRAS mutation was significantly associated with right-sided CRC and higher histology grade in 39/151 (25.83%) and 24/151 (16.44%) samples, respectively. PIK3CA mutation was significantly associated with female sex and lower levels of tumor-infiltrating lymphocytes in 62/107 (57.94%) and 26/107 (30.23%) samples, respectively. KRAS and PIK3CA mutations did not significantly affect overall survival (120 months) in LS and non-LS patients. The high probability of LS in Indonesian CRC patients is associated with KRAS and PIK3CA mutations.

Triple Negative Breast Cancer: Molecular Subtype-Specific Immune Landscapes with Therapeutic Implications.

Triple Negative Breast Cancer (TNBC) is characterized by distinct molecular subtypes with unique biological and clinical features. This systematic review aimed to identify articles examining the differences in the tumor immune microenvironment (TIME) across different TNBC molecular subtypes. Six studies meeting inclusion criteria were analyzed, utilizing gene expression profiling and bioinformatic analyses to classify TNBC samples into molecular subtypes, as well as immunohistochemistry and cell deconvolution methods to characterize the TIME. Results revealed significant heterogeneity in immune cell composition among TNBC subtypes, with the immunomodulatory (IM) subtype demonstrating robust immune infiltration, composed mainly of adaptive immune cells along with an increased density of CTLA-4+ and PD-1+ TILs, high PD-L1 tumor cell expression, and upregulation of FOXP3+ Tregs. A more immunosuppressive TIME with a predominance of innate immune cells and lower levels of tumor-infiltrating lymphocytes (TILs) was observed in luminal androgen receptor (LAR) tumors. In mesenchymal stem-like (MSL) tumors, the TIME was mainly composed of innate immune cells, with a high number of M2 tumor-associated macrophages (TAMs), while the BL and M tumors displayed poor adaptive and innate immune responses, indicating an "immune-cold" phenotype. Differential activation of signaling pathways, genomic diversity, and metabolic reprogramming were identified as contributors to TIME heterogeneity. Understanding this interplay is crucial for tailoring therapeutic strategies, especially regarding immunotherapy.

Prognostic significance of tumor-infiltrating lymphocytes in predicting outcome of distal cholangiocarcinoma in Thailand.

Patients with distal cholangiocarcinoma (dCCA) generally have poor outcomes because of late presentation and diagnosis. Therefore, prognostic factors for predicting outcomes are essential to improve therapeutic strategies and quality of life. Tumor-infiltrating lymphocytes (TILs) have been reported as a prognostic predictor in several cancers. However, their role in dCCA is still unclear. This study aimed to evaluate the association of TILs with outcome in patients with dCCA. Fifty-two patients were evaluated for the percentage rate of TILs in their cancers, and a median TIL level was used to divide the patients into two groups. Survival, multivariate, and correlation analyses were performed to determine the prognostic factors. Results showed that a low TIL level was associated with poor survival. Multivariate analysis revealed TILs as an independent factor for poor outcome. Moreover, TILs were markedly correlated with growth patterns, and both were applied to classify patients with dCCA. Subgroups of TILs with growth pattern incorporation improved stratification performance in separating good from poor patient outcomes. This study suggested that TILs could be a prognostic factor for predicting survival and for clustering patients with dCCA to improve prognostication capability. This finding may be incorporated into a new staging system for stratifying dCCA in Thailand.

Immune cell profiles in the tumor microenvironment of early-onset, intermediate-onset, and later-onset colorectal cancer.

Despite heightened interest in early-onset colorectal cancer (CRC) diagnosed before age 50, little is known on immune cell profiles of early-onset CRC. It also remains to be studied whether CRCs diagnosed at or shortly after age 50 are similar to early-onset CRC. We therefore hypothesized that immune cell infiltrates in CRC tissue might show differential heterogeneity patterns between three age groups (< 50 "early onset," 50-54 "intermediate onset," ≥ 55 "later onset"). We examined 1,518 incident CRC cases with available tissue data, including 35 early-onset and 73 intermediate-onset cases. To identify immune cells in tumor intraepithelial and stromal areas, we developed three multiplexed immunofluorescence assays combined with digital image analyses and machine learning algorithms, with the following markers: (1) CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 for T cells; (2) CD68, CD86, IRF5, MAF, and MRC1 (CD206) for macrophages; and (3) ARG1, CD14, CD15, CD33, and HLA-DR for myeloid cells. Although no comparisons between age groups showed statistically significant differences at the stringent two-sided α level of 0.005, compared to later-onset CRC, early-onset CRC tended to show lower levels of tumor-infiltrating lymphocytes (P = 0.013), intratumoral periglandular reaction (P = 0.025), and peritumoral lymphocytic reaction (P = 0.044). Compared to later-onset CRC, intermediate-onset CRC tended to show lower densities of overall macrophages (P = 0.050), M1-like macrophages (P = 0.062), CD14+HLA-DR+ cells (P = 0.015), and CD3+CD4+FOXP3+ cells (P = 0.039). This hypothesis-generating study suggests possible differences in histopathologic lymphocytic reaction patterns, macrophages, and regulatory T cells in the tumor microenvironment by age at diagnosis.

Abstract SY17-02: Multiantigen vaccines for colon cancer prevention

Abstract Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US when men and women are combined. While overall CRC incidence has declined over the years, there has been an increase in CRC diagnosis in young and middle-aged adults. The US Preventive Services Task Force has recently issued draft recommendations for CRC screening to begin at 45 years of age instead of the previously recommended age of 50 for asymptomatic healthy individuals, who are at average risk of CRC, i.e. without a family history of hereditary CRC syndromes such as Lynch syndrome and familial adenomatous polyposis, or with no prior diagnosis of CRC, adenomatous polyps, inflammatory bowel disease. While the evidence supports that CRC-screening and early detection confers a substantial benefit, additional CRC prevention strategies can greatly help reduce the cancer burden in the US and around the world. A number of previous studies have shown that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of cancers, including CRC. However, their extended use can be associated with serious side effects, including gastrointestinal bleeding. Safer and more efficacious preventive approaches are needed for durable long-term CRC prevention. The majority of newly diagnosed CRC are non-familial (sporadic) and non-hypermutated/microsatellite-stable (MSS). Compared to CRC with high microsatellite instability, MSS CRC and adenomas have significantly lower somatic mutation frequencies, thus lower neoantigen load. Furthermore, MSS CRC have generally lower levels of tumor-infiltrating lymphocytes (TILs), higher density of myeloid derived suppressor cells (MDSC), and downregulation of HLA molecules. These are characteristic of immunologically “cold” tumors, making it highly challenging to immunologically control tumor growth. If cancer vaccines can successfully prime the immune system, in particular before the development of invasive cancer, vaccine-induced adaptive antitumor immunity may render “cold” tumors “hot” and achieve a favorable tumor control. One of the key questions, however, is what tumor antigens can be targeted by vaccines if tumors have lower levels of neoantigens that are known to elicit robust antitumor immune responses. Another approach for cancer vaccine-mediated immune priming is to target tumor associated antigens (TAAs). Unlike tumor-specific neoantigens, TAAs are self-antigens that are overexpressed in tumors, but may also be expressed in normal cells at various levels. Therefore, it is highly critical to identify T cell epitopes that break tolerance and help elicit effective antitumor immunity. Clinically beneficial antitumor immunity is characterized by high-density infiltrates of effector CD8+ cytotoxic T lymphocytes and effector memory T cells and the low abundance of immunosuppressive elements (e.g. regulatory T cells, MDSC, and M2-polarized tumor-associated macrophages) in the tumor microenvironment. Disis and colleagues from University of Washington have previously established a systematic and stepwise approach to identify Th1-selective epitopes for efficacious cancer vaccines while eliminating Th2-epitopes. They have shown cancer vaccines targeting TAAs thus developed could elicit robust Th1 immune response associated with antitumor effects. The NCI PREVENT Cancer Preclinical Drug Development Program (PREVENT) is a peer-reviewed agent development program focused on preclinical development of innovative interventions, including cancer vaccines and drugs, for precision cancer prevention-interception towards clinical applications (https://prevention.cancer.gov/major-programs/prevent-cancer-preclinical). PREVENT and Disis team collaborated on the development of a multi-antigen multi-peptide colon cancer vaccine, named Colovac, for immunoprevention of CRC. It consists of highly immunogenic Th1-promoting epitopes from three TAAs that are selected through CRC genomic database and literature search. TAAs selected are overexpressed in CRC, known to play a role in CRC oncogenesis, and associated with poor disease outcomes. This presentation will cover the background of Colovac development, preclinical antitumor efficacy data on Colovac used alone or in combination with naproxen, characterization of immune correlates of protection, and current ongoing development efforts toward clinical trials. Citation Format: Shizuko Sei. Multiantigen vaccines for colon cancer prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY17-02.

Relationships between pathological factors and long-term outcomes in patients enrolled in two prospective randomized controlled trials comparing the efficacy of oral tegafur\u2013uracil with CMF (N\xb7SAS-BC\xa001 trial and CUBC trial)

PurposeTo evaluate the efficacies of cyclophosphamide, methotrexate, and fluorouracil (CMF) and tegafur–uracil (UFT) as adjuvant therapy in patients with resected stage I–IIIA breast cancer by immunohistochemistry (IHC)-based subtype and to determine the relationships between clinicopathological factors and long-term outcomes.MethodsA pooled analysis of the randomized controlled N·SAS-BC 01 and CUBC studies was conducted. Expression of hormone receptors (HRs; estrogen and progesterone receptors), human epidermal growth factor receptor 2 (HER2), and Ki67were assessed by IHC. Tumor-infiltrating lymphocytes (TILs) and nuclear/histological grades were determined by hematoxylin and eosin staining. Relapse-free survival (RFS) and overall survival (OS) were estimated by Kaplan–Meier analysis and hazard ratios were determined by Cox model adjusted for baseline tumor size and nodal status.ResultsA total of 689 patients (342 CMF and 347 UFT) were included in the analyses with a median follow-up of 11.1 years. There was no significant difference in RFS or OS between the two cohorts (RFS: 0.96 [95% confidence interval: 0.71–1.30], log-rank test p = 0.80; OS: 0.93 [0.64–1.35], p = 0.70). There was no difference in RFS or OS between the two cohorts for HR+/HER2− and HR+/HER2+ subtypes. RFS was significantly longer in patients treated with UFT compared with CMF in patients with HR−/HER2+ subtype (0.30 [0.10–0.88], p = 0.03). A high TILs level was associated with a better OS compared with low TILs level (p = 0.02).ConclusionsThis long-term follow-up study showed that RFS and OS were similar in patients with luminal-type breast cancer treated with CMF and UFT.

Differential gene expression of tumor-infiltrating CD8+ T cells in advanced versus early-stage colorectal cancer and identification of a gene signature of poor prognosis

BackgroundCytotoxic CD8+ T cell-mediated response is the most important arm of adaptive immunity, which dictates the capacity of the host immune response in eradicating tumor cells. Due to tumor intrinsic...

Abstract 1068: Tumor infiltrating lymphocytes (TIL) recognize a unique and diverse number of non-synonymous somatic mutations in patients with metastatic breast cancer

Abstract Introduction: Adoptive transfer of tumor infiltrating lymphocytes (TIL) can mediate long-term durable regression in patients with metastatic melanoma, a type of cancer which is characterized by a high number of mutated genes and pronounced lymphocytic infiltrate. In contrast, metastatic breast cancer expresses far fewer somatic mutations and may contain lower levels of TIL. This pilot study investigated the ability to identify immunogenic non-synonymous somatic mutations which can serve as targets for adoptively transferred autologous T cells into patients with metastatic breast cancer, refractory to other treatments. Methods: WES and RNAseq were performed on metastatic lesions resected in the Surgery branch, NCI, NIH from patients with metastatic breast cancer. Non-synonymous somatic mutations were identified and, in parallel, TIL from the same lesions were grown ex vivo in the presence of IL-2. The somatic mutations were tested for recognition by the autologous TIL using previously described functional assays, involving tandem mini-genes (TMG), long peptides or predicted minimal peptide approaches. For some patients, the mutation-reactive T cells were sorted by FACS and the respective TCR was identified by single cell sequencing. Results: Metastatic tumor lesions from 37 patients with breast cancer were studied and all of them were found to contain and express non-synonymous somatic mutations (range: 4-1788, median: 102). TIL were successfully grown ex vivo from the tumors of all patients. Following functional assays (IFN-γ secretion and 4-1BB/OX-40 upregulation), it was found that autologous TIL recognized at least one (range: 1-11, median: 3) mutated product in 25 of 37 patients (68%) tested. Seventy-five percent of those were recognized by CD4+ and 25% by CD8+ T cells. All identified immunogenic tumor mutations (n=88) were unique and not shared by other patients. Sixty-four unique TCR pairs were isolated from the reactive cells and verified to recognize 30 immunogenic tumor mutations (range 1-7 TCRs/neoantigen). Conclusions: Patients with metastatic breast cancer contain a substantial number of non-synonymous somatic mutations and mutation-reactive TIL were found in the majority of those patients. The immunogenicity of tumor-specific mutations in metastatic breast cancer can be the platform for a highly personalized adoptive T cell transfer of selected TIL or mutation-reactive TCR transduced T cells targeting those tumor mutated genes. Citation Format: Nikolaos Zacharakis, Peter Kim, Paul Robbins, Jared Gartner, Todd Prickett, Victoria Hill, Biman Paria, Steven Feldman, Stephanie Goff, Steven Rosenberg. Tumor infiltrating lymphocytes (TIL) recognize a unique and diverse number of non-synonymous somatic mutations in patients with metastatic breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1068.

Abstract P5-04-13: Triple negative breast cancer: Expression of immuno-oncology treatment targets and prevalence of tumor infiltrating lymphocytes in paired primary tumors and metastases

Abstract Introduction: There is extensive research into immune-oncology (IO) treatment targets for triple negative breast cancer (TNBC). However, little knowledge exits on variations in expression levels of IO targets between paired primary tumors (PT) and metastases (MT) in TNBC. Objectives: To compare expression levels of IO drug targets in paired PT and distant MT from TNBC patients. PD-L1 protein expression was examined immunohistochemically, as well as differences in levels of tumor infiltrating lymphocytes (TILs). Material and methods:552 patients were primarily operated for TNBC at 2 university hospitals in Denmark between 2004 and 2014. Of these, samples from 22 patients were available from both PT (22 samples) and distant MT (24 samples, with 2 chronologically separate metastases for two patients). Localizations of metastases included 9 brain, 1 skin and 1 lymph node (both not regional), 2 bone, 5 liver, 2 soft tissue, 1 lung, and 1 adrenal gland. Gene expression analyses were performed on the Ion Torrent S5XL system, using the Oncomine Immune Response Research Assay. PD-L1 expression was evaluated immunohistochemically using the 28-8 clone (pharmdX). Cut-off levels for PD-L1 expression were 1% positive tumor cells. TILs were evaluated in accordance with guidelines from the International Immuno-Oncology Biomarker Working Group. Results: Gene expression levels of 29 established IO drug targets were tested on 18 of the 22 TNBC patients with matched PTs and MTs (Table 1). 4 genes showed significant downregulation in MTs compared to PTs: IDO1 (p=0.01), CXCR4 (p=0.01), KIR2DL1 (p=0.05) and TNFRSF9 (p=0.03). However, other important IO targets such as CTLA4, STAT3, TIGIT, and TNSFRSF18 (GITR) were not significantly different between PT and MT. CD276 (B7-H3), PD-1, IL2 and LAG3 showed a tendency towards significance (p= 0.08, 0.07, 0.05, 0.08), with LAG3 being the only gene upregulated in MT compared to PT. TILs were evaluated for all PTs and MTs. TILs in PTs ranged from 1 to 40% (median=13%). TILs in MTs ranged from 1 to 60% (median=5%). There was no significant overall change in TILs from PT to MT (p=0.2). However, 9 patients had a difference in TILs between PT and MT of &amp;gt; ±10% (-20 - +30). PD-L1 immunohistochemical evaluation was possible for both PT and MT in 20 cases. There was no significant overall change in PD-L1 expression (p=0.39). However, 4 patients with positive PTs, had negative MTs, and 4 patients with PD-L1 negative PTs, had positive MTs. Discussion: This is, to our knowledge, one of the largest studies of gene expression of IO drug targets in TNBC matched PTs and MTs. We show significant differences in gene expression levels for IDO1, CXCR4, KIR2DL1 and TNFRSF9, pointing to a generally less immune-active environment in MTs. This was also corroborated by lower levels of TILs in MTs, although these findings were not significant. For PD-L1 protein expression, we found that PD-L1 expression can change between PT and MT. In the clinical setting, treatment decisions are often based upon expression levels in a single biopsy or surgical specimen. Intra-patient heterogeneity should be taken into account in the diagnostic setting, and when making treatment decisions. Table 1IO drug targetRatio (Primary/metastasis)P-valueIDO19.65 (1.68-54.95)0.01CXCR41.83 (1.17-2.87)0.01KIR2DL12.17 (1.01-4.69)0.05TNFRSF97.11 (1.21-41.93)0.03CD276 (B7H3)1.51 (0.94-2.39)0.08PDCD1 (PD1)3.32 (0.88-12.64)0.07IL22.87 (0.99-8.28)0.05LAG30.28 (0.07-1.16)0.08CTLA41.96 (0.45-8.51)0.35STAT31.21 (0.92-1.60)0.16TIGIT1.87 (0.25-14.03)0.53TNFRSF18 (GITR)0.38 (0.06-2.20)0.26 Citation Format: Elisabeth S Stovgaard, Tim S Poulsen, Eva Balslev, Dorte L Nielsen, Anne Roslind, Maj-Lis Talman, Iben Kümler, Ib J Christensen, Estrid Høgdall. Triple negative breast cancer: Expression of immuno-oncology treatment targets and prevalence of tumor infiltrating lymphocytes in paired primary tumors and metastases [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-04-13.

Intrinsic Prognostic Impact of Tumor-infiltrating Lymphocytes in Systemically Untreated Patients With Early-stage Triple-negative Breast Cancer

The prognostic value of tumor-infiltrating lymphocytes (TILs) in curatively resected, but systemically untreated early-stage triple-negative breast cancer (TNBC) was investigated. Patients with systemically untreated early TNBC between 1999 and 2012 were retrospectively reviewed. A low TIL level was defined as the presence of ≤10% stromal TILs Relapses were classified into locoregional and distant relapse. The primary endpoint was breast cancer-specific survival (BCSS). In 72 patients, the median TIL value was 10%, and low TIL status was found in 54.2%. Patients with pT1 and nodal-positive disease constituted 75% and 11.1%, respectively. With a median follow-up of 99 months, 26.4% patients experienced relapse; local in 63.2%, distant in 36.8%, and 9.7% died of disease progression. A low TIL level was significantly associated with distant relapse (p=0.013), and inferior 10-year BCSS, which was consistently observed in patients with T1a/b or N0 disease. A low TIL level seems to be an intrinsic prognostic factor in systemically untreated patients with early-stage TNBC, even in the T1a/bN0 subset.

Presence of tertiary lymphoid structures determines the level of tumor-infiltrating lymphocytes in primary breast cancer and metastasis

The level of tumor-infiltrating lymphocytes and presence of tertiary lymphoid structures are significant prognostic and predictive factors in primary breast cancer. However, the understanding about differences in tumor-infiltrating lymphocytes and tertiary lymphoid structures at various metastatic sites or between primary breast tumors and metastatic sites is limited. A total of 335 cases of metastatic breast cancer from four metastatic sites (lung, liver, brain, and ovary) were included. We analyzed the percentages of tumor-infiltrating lymphocytes and presence of tertiary lymphoid structures in the primary and metastatic sites. The mean level of tumor-infiltrating lymphocytes in the lung metastases was higher than in the liver, brain, ovary, and matched primary tumors, while metastatic tumors of the liver and brain showed lower levels of tumor-infiltrating lymphocytes than primary tumors. Tertiary lymphoid structures were only found in the lung and liver, and in cases of brain metastases the change of tertiary lymphoid structures from present to absent significantly affected the level of tumor-infiltrating lymphocytes in metastases compared with that in matched primary tumors. Patients with a lower histological grade, hormone receptor positivity in primary tumors and metastases, a lower level of tumor-infiltrating lymphocytes and absence of tertiary lymphoid structures in primary tumors, a higher level of tumor-infiltrating lymphocytes and presence of tertiary lymphoid structures in metastases, and lung metastases showed significantly better overall survival. Our results showed that metastatic breast tumors in the lung had more tumor-infiltrating lymphocytes than did tumors at other sites and matched primary tumors. In addition, the presence of tertiary lymphoid structures in metastatic sites is a critical factor for the level of tumor-infiltrating lymphocytes.

Tumor Infiltrating Lymphocytes in Breast Cancer Patients with Progressive Disease during Neoadjuvant Chemotherapy.

A minority of breast cancer (BC) patients progress during neoadjuvant chemotherapy (NCT). The aim of this study was to assess the value of Tumor infiltrating lymphocytes (TILs) in such a high-risk population where valid biomarkers are eagerly needed. A retrospective review identified BC patients who either progressed during NCT or achieved a pathologic complete response (pCR). An experienced BC pathologist semi-quantified stromal TILs in pre-treatment core biopsies using hematoxylin and eosin stained slides. The primary outcome was to compare the levels of TILs between the 2 groups as a continuous and categorical variable using the t-test and X2 test as appropriate. The secondary outcome was to compare survival outcomes between patients with high versus low TILs level using the log-rank test. Fifty patients were successfully identified and assessed for TILs: 21 progressed during NCT and 29 had a pCR. Patients with progressive disease were older with more advanced disease (p = 0.03, p = 0.0001 respectively). A significantly lower mean level of TILs was found in patients with progressive disease compared to patients with pCR: 14.3% (Standard Deviation (SD): 16.9) versus 32.8% (SD: 31), p = 0.01). The level of TILs was neither associated with baseline characteristics nor with survival outcomes. BC patients progressing during NCT have low TILs levels compared to patients with pCR. Prospective studies are needed to establish the utility of TILs as early biomarkers of tumor response, particularly in patients with disease progression who need novel treatment approaches.

Agonist immunotherapy restores T cell function following MEK inhibition improving efficacy in breast cancer

The presence of tumor-infiltrating lymphocytes in triple-negative breast cancers is correlated with improved outcomes. Ras/MAPK pathway activation is associated with significantly lower levels of tumor-infiltrating lymphocytes in triple-negative breast cancers and while MEK inhibition can promote recruitment of tumor-infiltrating lymphocytes to the tumor, here we show that MEK inhibition adversely affects early onset T-cell effector function. We show that α-4-1BB and α-OX-40 T-cell agonist antibodies can rescue the adverse effects of MEK inhibition on T cells in both mouse and human T cells, which results in augmented anti-tumor effects in vivo. This effect is dependent upon increased downstream p38/JNK pathway activation. Taken together, our data suggest that although Ras/MAPK pathway inhibition can increase tumor immunogenicity, the negative impact on T-cell activity is functionally important. This undesirable impact is effectively prevented by combination with T-cell immune agonist immunotherapies resulting in superior therapeutic efficacy.

Tumor-infiltrating lymphocytes in breast cancer predict the response to chemotherapy and survival outcome: A meta-analysis

Tumor-infiltrating lymphocytes (TILs) influence tumor prognosis and the chemotherapeutic response. Here, we quantified the clinical relevance of TILs, including the effect of TILs on lymphocyte subpopulations and assessed their consistency in breast cancer. We searched published literature from January 2000 to January 2016. The main parameters analyzed were pathological complete response (pCR) and survival outcome following chemotherapy in patients with breast cancer. Pooled odds ratio (OR) or relative risk (RR) values with 95% confidence intervals (CIs) were computed using random and fixed-effects models. Subgroup and heterogeneity analyses were also conducted. Twenty-three studies, which included 13,100 patients, met the inclusion criteria. The pooled results showed that TILs were associated with clinicopathological parameters of biologically aggressive phenotypes, such as high tumor grade or estrogen/progesterone receptor negativity, but they were not correlated with human epidermal growth factor receptor-2 expression. Moreover, a high TIL level was associated with a significantly improved pCR rate compared with a low TIL level (OR, 2.81; P < 0.001), particularly in the triple-negative breast cancer subtype (OR, 4.67; P < 0.001). An analysis of lymphocyte subpopulations showed that infiltration by CD8 lymphocytes, but not by CD4 lymphocytes and Foxp3 cells, was associated with a high pCR rate. Furthermore, a high TIL level was associated with significantly longer disease-free survival and overall survival. Our present meta-analysis indicates that an increased number of TILs predicted pCR to chemotherapy and improved survival. A high TIL level, characterized mainly by the infiltration of CD8 lymphocytes, is a strong predictive and prognostic factor.