Immune-response markers and actual response to immune-oncology therapy in uterine serous carcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5590-5590
Author(s):  
Nathaniel L. Jones ◽  
Sharon Wu ◽  
Joanne Xiu ◽  
Amaranta Craig ◽  
Gina Mantia-Smaldone ◽  
...  
Keyword(s):  
T Cells ◽  
Median Survival ◽  
Survival Benefit ◽  
Immune Cell ◽  
Statistical Significance ◽  
Serous Carcinoma ◽  
Myeloid Dendritic Cells ◽  
Primary Tumors ◽  
Uterine Serous Carcinoma ◽  
Immune Oncology

5590 Background: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer with poor prognosis and limited treatment options. Immune-oncology (IO) agents have shown promise USC, however data is limited regarding which patients benefit most from IO therapy. In other malignancies, PD-L1, MSI-H status and high TMB have been predictive of IO response. We sought to characterize the immune profiles of USC and investigate treatment response to IO therapy. Methods: Tumor samples were analyzed using Nex-Gen sequencing of the DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ).PD-L1 IHC used SP-142 (cut-off >1%). MSI was tested by FA, IHC and NGS. TMB was measured by totaling somatic mutations per tumor (high > 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. Real-world overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank sum test and p values adjusted for multiple comparisons (q) to be < 0.05. Results: Molecular analysis was performed on 2,806 USC tumors. The median age was 67 years. 65.3% were from primary tumors, 34.7% from metastatic sites. In total, 92 patients were treated with IO therapy and had a significantly longer median survival than those not treated with IO (months: 59.6 vs 31.2; HR(95% CI): 0.38(0.24-0.61) p < 0.001), resulting in a survival advantage of 867 days. PD-L1 expression was present in 19.1% of cases, but only 2.3% of tumors were MSI-H and 4.2% were TMB-H. Patients with these markers trended toward a better median survival, but this was not significant; PD-L1 (months: 34.4 vs 31.2; HR(95% CI): 0.90 (0.74-1.1), MSI-H (OS not yet reached vs 31.6 months; HR(95% CI): 0.69(0.38-1.25) and TMB-H (months: 36.4 vs 31.6; HR(95% CI): 0.84(0.50-1.39). Regarding the immune microenvironment, the most common infiltrating immune cells were M2 Macrophages (5.35%), B cells (4.71%), myeloid dendritic cells (3.45%), NK cells (2.94%) and regulatory T cells (1.59%). There were few CD8 T cells and non-regulatory CD4 T cells. Conclusions: IO therapy was associated with a median survival benefit of more than 2 years in USC. We did not identify any prognostic markers of IO-therapy response. MSI-H and TMB-H are rare in USC, but PD-L1 is present in nearly 20% of cases. Notably these markers did predict a significant survival benefit, which has important clinical implications. Further study is warranted.

Molecular determinants of response to immune-oncology therapy in uterine carcinosarcoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5582-5582
Author(s):  
Annelise M. Wilhite ◽  
Sharon Wu ◽  
Joanne Xiu ◽  
Britt Kristina Erickson ◽  
Rodney Paul Rocconi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Immune Cell ◽  
Statistical Significance ◽  
Treatment Options ◽  
Fold Increase ◽  
Molecular Profile ◽  
Uterine Carcinosarcoma ◽  
Chi Square ◽  
Primary Tumors ◽  
Immune Oncology

5582 Background: Uterine carcinosarcoma (UCS) is subtype of endometrial cancer (EC) with aggressive behavior and poor prognosis. UCS has not traditionally been included in EC clinical trials and treatment options are limited. Immune-oncology (IO) therapy has shown promise UCS, but it is unknown which patients benefit most. We sought to identify immunogenic markers in UCS and explore treatment response to IO therapy. Methods: Tumor samples were analyzed using Nex-Gen sequencing of the DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ).PD-L1 IHC used SP-142 (cut-off >1%). MSI was tested by FA, IHC and NGS. TMB was measured by totaling somatic mutations per tumor (high > 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. Overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank sum test and p values adjusted for multiple comparisons (q) to be <0.05. Results: A total of 1,144 UCS tumors underwent comprehensive tumor profiling. 68.4% of samples were obtained from primary tumors and 31.6% from metastatic sites. 21.6% of tumors expressed PD-L1, 8.5% were TMB-H and 6.8% were MSI-H/MMRd. UCS patients treated with IO had longer median overall survival than those not treated with IO (months: 31.2 vs 19.4; HR(95% CI): 0.39 (0.17-0.76) p=0.005). Median OS was also increased for dMMR/MSI-H (OS not yet reached vs 18.9 months); HR(95% CI): 0.56 (0.36-0.92) p=0.019) and TMB-H (OS not yet reached vs 18.9 months); HR(95% CI): 0.62 (0.38-0.99) p=0.047). More patients are needed to determine if these markers predict response to IO therapy. The most common mutations in UCS led to pathway dysregulation in the PI3K, RAS, chromatin remodeling, HR, and WNT pathways. dMMR/MSI-H tumors have distinct molecular profiles compared to MSS tumors (table). Additionally, dMMR/MSI-H tumors had higher TMB (96.9% vs 2.2%, q<0.01) and increased frequency of PDL-1 (23.6% vs 13.8%; q=0.04). Immune checkpoint genes were more often expressed in MSI-H tumors, though this was non-significant except for IFNG (4.66-fold increase; q=0.01). Conclusions: IO therapy is associated with improved survival in USC. MSI and TMB are markers of improved OS in patients with UCS. MSI tumors have a distinct molecular profile compared to MSS tumors, and they appear to be more immunogenic, which could contribute to the improved survival seen in patients who received IO therapy.[Table: see text]

Exploring molecular profiles and survival in hormone receptor-positive uterine serous carcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5579-5579
Author(s):  
Amaranta Craig ◽  
Annelise M. Wilhite ◽  
Sharon Wu ◽  
Joanne Xiu ◽  
Gina Mantia-Smaldone ◽  
...  
Keyword(s):  
Hormone Therapy ◽  
Hormone Receptor ◽  
Immune Cell ◽  
Statistical Significance ◽  
Hazard Ratio ◽  
Receptor Expression ◽  
Serous Carcinoma ◽  
Molecular Profile ◽  
Uterine Serous Carcinoma ◽  
Molecular Profiles

5579 Background: Hormone receptor (HR) positivity has been reported as a good prognostic indicator in endometrial cancer. This study investigated estrogen receptor (ER) and progesterone receptor (PR) positivity as indicators of platinum response and improved survival in uterine serous carcinoma (USC), and determined differences in molecular profiles between these tumors and hormone receptor negative tumors. Methods: Tumor profiling was done with immunohistochemistry (IHC), next generation sequencing (NGS), and whole transcriptome sequencing (WTS). PD-L1 expression was determined by IHC using SP-142 (cut-off >1%). Microsatellite instability (MSI) status was evaluated with IHC and NGS, and tumor mutational burden (TMB) by totaling somatic mutations per tumor (high if > 10 mutations/ MB). Immune-cell fraction was determined with QuantiSeq. We used insurance claims data to calculate Kaplan-Meier estimates for overall survival (OS). Statistical significance was determined with chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons. Results: 2806 USC tumors were available for molecular profiling with 717 HR+/966 HR-, 1559 ER+/1059 ER- and 805 PR+/1809 PR-. Median OS for HR+ patients was longer than patients who were HR- regardless of treatment (1152 v 797 days; hazard ratio 0.68, 95% CI 0.58-0.80, p < 0.01). This OS benefit of HR positivity remained for patients receiving platinum therapy (1134 v 889 days; hazard ratio 0.75, 95% CI 0.58-0.98, p < 0.01). HR+ status trended towards improved OS in those treated with hormone therapy (407 vs 771 days, hazard ratio 0.78, 95% CI 0.59-1.02, p = 0.07). In addition to increased androgen receptor expression (54.2 vs 6.2%, p = < 0.001), PTEN mutations were more common in the HR+ group (10.3 vs 5.1%, p = 0.016). This resulted in in more frequent alterations of the PI3K pathway when compared to HR- tumors 64.5 vs 52.2%, p = < 0.001). PD-L1, TMB, and MSI status were similar between the two cohorts. Checkpoint inhibitor gene expression was notable for higher IDO expression in the HR+ group, but lower CD80, CD86, HAVCR2, IFNG, and PDC1 expression. The immune micro-environment was notable for less B-cells and M1 macrophages, but more M2 macrophages. Breaking the ER and PR positive cohort down to individual expression of each gene resulted in similar OS and molecular findings. Conclusions: HR positivity is associated with improved survival in allcomers with USC and those treated with platinum therapy, and there was a trend to improved OS with hormone therapy. More data is needed to determine if HR status is a prognostic marker for IO treatment response. This cohort had a distinct molecular profile compared to HR- tumors.

scholarly journals IMMU-19. TARGETING GLIOBLASTOMA IMMUNOSUPPRESSION AND TREATMENT RESISTANCE WITH IBRUTINIB IN COMBINATION WITH STEREOTACTIC RADIATION AND IMMUNE CHECKPOINT BLOCKADE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii108-ii108
Author(s):  
Jayeeta Ghose ◽  
Baisakhi Raychaudhuri ◽  
Kevin Liu ◽  
William Jiang ◽  
Pooja Gulati ◽  
...  
Keyword(s):  
T Cells ◽  
Combination Therapy ◽  
Median Survival ◽  
Immune Checkpoint ◽  
Survival Benefit ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Control Group ◽  
Triple Combination ◽  
Triple Combination Therapy

Abstract BACKGROUND Glioblastoma (GBM) is associated with systemic and intratumoral immunosuppression. Part of this immunosuppression is mediated by myeloid derived suppressor cells (MDSCs). Preclinical evidence shows that ibrutinib, a tyrosine kinase inhibitor FDA approved for use in chronic lymphocytic leukemia and known to be CNS penetrant, can decrease MDSC generation and function. Also, focal radiation therapy (RT) synergizes with anti-PD-1 therapy in mouse GBM models. Thus, we aimed to test the combination of these approaches on immune activation and survival in a preclinical immune-intact GBM mouse model. METHODS C57BL/6 mice intracranially implanted with the murine glioma cell line GL261-Luc2 were divided into 8 groups consisting of treatments with ibrutinib, RT (10 Gy SRS), or anti-PD-1 individually or in each combination (along with a no treatment control group). Immune cell subset changes (flow-cytometry) and animal survival (Kaplan-Meier) were assessed (n=10 mice per group). RESULTS Median survival of the following groups including control (28 days), ibrutinib (27 days), RT (30 days) or anti-PD-1 (32 days) showed no significant differences. However, a significant improvement in median survival was seen in mice given combinations of ibrutinib+RT (35 days), ibrutinib+anti-PD-1 (38 days), and triple therapy with ibrutinib+RT+anti-PD-1 (48 days, p &lt; 0.05) compared to controls or single treatment groups. The reproducible survival benefit of triple combination therapy was abrogated in the setting of CD4+ and CD8+ T cell depletion. Contralateral intracranial tumor re-challenge in long-term surviving mice suggested generation of tumor-specific immune memory responses. The immune profile of the tumor microenvironment (TME) showed increased cytotoxic CD8+ T cells and decreased MDSCs and regulatory T cells in the triple combination therapy mice compared to controls. CONCLUSION The combination of ibrutinib, focal RT, and anti-PD-1 immune checkpoint blockade led to a significant survival benefit compared to controls in a preclinical model of GBM.

scholarly journals Immune classification of clear cell renal cell carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sumeyye Su ◽  
Shaya Akbarinejad ◽  
Leili Shahriyari
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Renal Cell ◽  
Cd4 T Cells ◽  
Immune Cell ◽  
Clear Cell ◽  
P Value ◽  
Cell Type ◽  
Primary Tumors ◽  
Immune Cell Type

AbstractSince the outcome of treatments, particularly immunotherapeutic interventions, depends on the tumor immune micro-environment (TIM), several experimental and computational tools such as flow cytometry, immunohistochemistry, and digital cytometry have been developed and utilized to classify TIM variations. In this project, we identify immune pattern of clear cell renal cell carcinomas (ccRCC) by estimating the percentage of each immune cell type in 526 renal tumors using the new powerful technique of digital cytometry. The results, which are in agreement with the results of a large-scale mass cytometry analysis, show that the most frequent immune cell types in ccRCC tumors are CD8+ T-cells, macrophages, and CD4+ T-cells. Saliently, unsupervised clustering of ccRCC primary tumors based on their relative number of immune cells indicates the existence of four distinct groups of ccRCC tumors. Tumors in the first group consist of approximately the same numbers of macrophages and CD8+ T-cells and and a slightly smaller number of CD4+ T cells than CD8+ T cells, while tumors in the second group have a significantly high number of macrophages compared to any other immune cell type (P-value $$<0.01$$ < 0.01 ). The third group of ccRCC tumors have a significantly higher number of CD8+ T-cells than any other immune cell type (P-value $$<0.01$$ < 0.01 ), while tumors in the group 4 have approximately the same numbers of macrophages and CD4+ T-cells and a significantly smaller number of CD8+ T-cells than CD4+ T-cells (P-value $$<0.01$$ < 0.01 ). Moreover, there is a high positive correlation between the expression levels of IFNG and PDCD1 and the percentage of CD8+ T-cells, and higher stage and grade of tumors have a substantially higher percentage of CD8+ T-cells. Furthermore, the primary tumors of patients, who are tumor free at the last time of follow up, have a significantly higher percentage of mast cells (P-value $$<0.01$$ < 0.01 ) compared to the patients with tumors for all groups of tumors except group 3.

scholarly journals 48 Immune environment correlates with NSCLC and CRC patient survival

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A55-A55
Author(s):  
Dannah Miller ◽  
Huong Nguyen ◽  
Kate Hieber ◽  
Charles Caldwell ◽  
Roberto Gianani
Keyword(s):  
T Cells ◽  
Image Analysis ◽  
Immune Cells ◽  
Survival Data ◽  
Immune Cell ◽  
Patient Survival ◽  
Machine Learning Algorithms ◽  
Primary Tumors ◽  
Cell Lung Carcinoma ◽  
Analysis Platform

BackgroundImmune cells within the tumor microenvironment (TME) play a vital role in regulating tumor progression. Therefore, immunotherapies that stimulate anti-tumor responses are of great interest for the treatment of various cancers. PD-L1 expression on immune cells is positively correlated with increased patient survival. Our hypothesis is that non-small cell lung carcinoma (NSCLC) and colorectal cancer (CRC) patients with high immune infiltration and greater amounts of anti-tumor immune cells within the tumor compartment have an increased time of survival compared to cancers with immune excluded or immune desert environments.MethodsOne NSCLC and one CRC tumor microarray (TMA) containing primary tumors, metastases, and normal tissue were stained via multiplex immunofluorescence (mIF) for 6 different immune markers: CD3, CD8, CD56, CD68, CD163, and PD-L1. This multiplex panel was designed to evaluate the immune cell population as well as tumor and immune cell PD-L1 status to aid in research for immunotherapies, specifically anti-PD-L1 therapies. The stained TMAs were analyzed utilizing Flagship Biosciences’ proprietary image analysis platform. Machine learning algorithms stratified cells as belonging to the tumoral or stromal space based on their cellular features. Core level expression data was pulled and represented on a whole-cohort basis. All staining and image analysis outputs were reviewed by a board-certified, MD pathologist. Kaplan-meier curves were generated based on survival data in relation to the levels of immune cells present within the tumor cores as well as the percentage of immune cells infiltrating into the tumor.ResultsThere is a clear correlation between patient survival and the presence or absence of various types of immune cells, including helper T cells, cytotoxic T cells, M1 macrophages, M2, macrophages, NK cells, as well as PDL1 expression on tumor and immune cells. Specifically, the increased presence of anti-tumor immune cells as well as increased expression of PD-L1 on immune cells within the tumor compartment correlates with an increase in patient survival.ConclusionsData generated through Flagship Biosciences’ image analysis platform showed a strong relationship between immune cell presence and localization and NSCLC and CRC patient survival. Altering the immune cells within the tumor to an anti-tumor immune environment could increase patient survival times. Combining immune checkpoint inhibitors with current FDA approved therapies for NSCLC and CRC are of interest to further extend patient survival. Further, utilizing Flagship Biosciences’ image analysis software to understand cancer immune microenvironments should be further utilized to aid in diagnosis and treatment decisions.

scholarly journals Identification of human immune cell subtypes most responsive to IL-1β–induced inflammatory signaling using mass cytometry

2021 ◽  
Vol 14 (673) ◽  
pp. eabc5763 ◽  
Author(s):  
Hema Kothari ◽  
Corey M. Williams ◽  
Chantel McSkimming ◽  
Fabrizio Drago ◽  
Melissa A. Marshall ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Human Peripheral Blood ◽  
Effector Memory ◽  
High Morbidity ◽  
Cytokine Storm ◽  
Mass Cytometry ◽  
Myeloid Dendritic Cells

IL-1β is a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19, and IL-1β blockade with anakinra and canakinumab during COVID-19 infection has entered clinical trials. Using mass cytometry of human peripheral blood mononuclear cells, we identified effector memory CD4+ T cells and CD4−CD8low/−CD161+ T cells, specifically those positive for the chemokine receptor CCR6, as the circulating immune subtypes with the greatest response to IL-1β. This response manifested as increased phosphorylation and, thus, activation of the proinflammatory transcription factor NF-κB and was also seen in other subsets, including CD11c+ myeloid dendritic cells, classical monocytes, two subsets of natural killer cells (CD16−CD56brightCD161− and CD16−CD56dimCD161+), and lineage− (Lin−) cells expressing CD161 and CD25. IL-1β also induced a rapid but less robust increase in the phosphorylation of the kinase p38 as compared to that of NF-κB in most of these immune cell subsets. Prolonged IL-1β stimulation increased the phosphorylation of the transcription factor STAT3 and to a lesser extent that of STAT1 and STAT5 across various immune cell types. IL-1β–induced production of IL-6 likely led to the activation of STAT1 and STAT3 at later time points. Interindividual heterogeneity and inhibition of STAT activation by anakinra raise the possibility that assays measuring NF-κB phosphorylation in response to IL-1β in CCR6+ T cell subtypes could identify those patients at higher risk of cytokine storm and most likely to benefit from IL-1β–neutralizing therapies.

scholarly journals Tumor Size Matters—Understanding Concomitant Tumor Immunity in the Context of Hypofractionated Radiotherapy with Immunotherapy

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 714
Author(s):  
Jean Philippe Nesseler ◽  
Mi-Heon Lee ◽  
Christine Nguyen ◽  
Anusha Kalbasi ◽  
James W. Sayre ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Tumor Regression ◽  
Experimental Models ◽  
Tumor Burden ◽  
Local Regression ◽  
Cell Content ◽  
Primary Tumors ◽  
The Impact

The purpose of this study was to determine the dynamic contributions of different immune cell subsets to primary and abscopal tumor regression after hypofractionated radiation therapy (hRT) and the impact of anti-PD-1 therapy. A bilateral syngeneic FSA1 fibrosarcoma model was used in immunocompetent C3H mice, with delayed inoculation to mimic primary and microscopic disease. The effect of tumor burden on intratumoral and splenic immune cell content was delineated as a prelude to hRT on macroscopic T1 tumors with 3 fractions of 8 Gy while microscopic T2 tumors were left untreated. This was performed with and without systemic anti-PD-1. Immune profiles within T1 and T2 tumors and in spleen changed drastically with tumor burden in untreated mice with infiltrating CD4+ content declining, while the proportion of CD4+ Tregs rose. Myeloid cell representation escalated in larger tumors, resulting in major decreases in the lymphoid:myeloid ratios. In general, activation of Tregs and myeloid-derived suppressor cells allow immunogenic tumors to grow, although their relative contributions change with time. The evidence suggests that primary T1 tumors self-regulate their immune content depending on their size and this can influence the lymphoid compartment of T2 tumors, especially with respect to Tregs. Tumor burden is a major confounding factor in immune analysis that has to be taken into consideration in experimental models and in the clinic. hRT caused complete local regression of primary tumors, which was accompanied by heavy infiltration of CD8+ T cells activated to express IFN-γ and PD-1; while certain myeloid populations diminished. In spite of this active infiltrate, primary hRT failed to generate the systemic conditions required to cause abscopal regression of unirradiated microscopic tumors unless PD-1 blockade, which on its own was ineffective, was added to the RT regimen. The combination further increased local and systemically activated CD8+ T cells, but few other changes. This study emphasizes the subtle interplay between the immune system and tumors as they grow and how difficult it is for local RT, which can generate a local immune response that may help with primary tumor regression, to overcome the systemic barriers that are generated so as to effect immune regression of even small abscopal lesions.

Effect of TCHL-based therapy on immune cell content in on-treatment, neoadjuvant-treated HER2-positive breast cancer patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 583-583
Author(s):  
Niamh M. Keegan ◽  
Sinead Toomey ◽  
Joanna Fay ◽  
Stephen F. Madden ◽  
Bruce Moran ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Immune Cell ◽  
Cell Populations ◽  
Breast Cancer Patients ◽  
Myeloid Dendritic Cells ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
The Impact ◽  
Positive Breast Cancer

583 Background: In the TCHL trial (NCT01485926) 78 women with HER2-positive breast cancer (BC) underwent neo-adjuvant treatment with either TCH (Docetaxel, Carboplatin, Trastuzumab) or TCHL (TCH + Lapatinib) therapy. Of the 78 patients, 24 consented to an optional on-treatment biopsy 20 days after 1 cycle of therapy. We analysed the impact of tumour infiltrating lymphocytes (TILs) on pathological complete response (pCR) and also determined the impact of TCH/TCHL therapy on immune cell modulation after 20 days of treatment. Methods: We assessed TIL and stromal lymphocytes (SL) counts using immunohistochemical staining with Haemotoxalyin+Eosin, AE1/AE3 and CD45 in formalin fixed paraffin embedded (FFPE) baseline biopsy samples and in fresh frozen (FF) biopsies taken 20-days post cycle 1 (Day-20) of TCH/TCHL. RNA libraries were generated, using the Truseq mRNA library prep kit on the Neoprep platform and sequenced on the NextSeq 500. We measured the transcriptomic profile of 8 pre and on-treatment sample pairs and then used the Microenvironment Cell Populations (MCP)-counter method to measure the abundance of 10 immune cell populations (T cells, CD8 T cells, cytotoxic lymphocytes, NK cells, B lineage, myeloid dendritic cells, neutrophils, endothelial cells and fibroblasts). Results: We found that higher baseline levels of TILs (p = 0.045) but not SL were associated with an increased likelihood of a patient achieving a pCR to TCH/L based therapy. We found in day 20 on-treatment biopsies of women that subsequently went onto have a pCR that levels of SLs but not TILs were significantly higher (p = 0.049) than in those women who did not have a pCR. Finally we found significant increases in the level of monocytes (p = 0.05) and fibroblasts (p = 0.01), but not other immune cell populations, in the day 20 on-treatment biopsies in comparison with the mutated pre-treatment biopsies. Conclusions: In our study baseline TILs but not SLs have a predictive role in the likelihood of a patient achieving a pCR. We also found that TCHL based therapy significantly altered both monocytes and fibroblasts, indicating a possible role for these immune subtypes in response to TCHL therapy.

CDK12 upregulation and adverse correlation with tumor-associated immune cell infiltrates in prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 181-181
Author(s):  
Marie C. Hupe ◽  
Anne Offermann ◽  
Cleopatra Schreiber ◽  
Axel Stuart Merseburger ◽  
Sven Perner
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Immune Cell ◽  
Locally Advanced ◽  
Survival Rates ◽  
Distant Metastases ◽  
Genetic Alterations ◽  
Primary Tumors ◽  
Locally Advanced Tumors ◽  
Advanced Tumors

181 Background: Biallelic loss of CDK12 has recently been identified as a novel subtype of prostate cancer (PCa). CDK12 altered PCa associates with elevated neoantigen burden and thus may be suitable for checkpoint inhibition. Up to now, data about CDK12 refer to its genetic alterations in PCa while its characterization on protein level and its association with tumor infiltrating T-cells are lacking. Methods: Immunohistochemistry (IHC) for CDK12 was performed on a PCa cohort including 74 benigns, 391 primary tumors from 222 patients, 63 locally advanced tumors, 92 lymph node (LN) metastases, and 56 distant metastases. CDK12 was categorized into negative, weak, moderate and high expression. Density of tumor associated T-cells per tumor area was assessed by IHC for CD3 and graduated into negative (<1%), slight (1-5%), weak (5-10%), moderate (10-50%) and high (>50%). Results: CDK12 significantly increases during PCa progression showing highest levels in LN and distant metastases while benign samples harbor no or weak CDK12 expression (ANOVA p<0.001). Kaplan-Meier curve reveals 5-year-biochemical recurrence free survival rates of 89.5%, 69.1%, 59.1% and 20.0% for primary tumors expressing no, weak, moderate and high CDK12 (log-rank p=0.05). High CDK12 expression significantly associates with attenuated tumor associated T-cells (p=0.009) revealing CD3 negativity in 64.7% of CDK12 high expressing tumors. Intratumoral CDK12 and density of CD3 positive T-cells correlates adversely in particular in locally advanced tumors (p=0.007). Overall, tumor associated T-cells are significantly reduced in distant metastases compared to local PCa (p<0.001). Conclusions: Our study highlights the prognostic potential of CDK12 for PCa and its overexpression in advanced tumors. Of note, CDK12 overexpressing tumors can be designated as immunologic “cold” tumors which is in line with their more aggressive phenotype. Concordantly, distant metastases show attenuated tumor associated T-cells supporting the poor response to immunotherapy.

Intratumoral immune reaction: A novel paradigm for cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 471-471 ◽  
Author(s):  
J. Galon ◽  
B. Mlecnik ◽  
A. Kirilovsky ◽  
G. Bindea ◽  
M. Tosolini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Cancer Patients ◽  
Immune Reaction ◽  
Immune Cell ◽  
Human Cancer ◽  
Effector Memory ◽  
Tumor Escape ◽  
Primary Tumors ◽  
The Impact

471 Background: To date the anatomic extent of tumor (TNM classifications) has been by far the most important factors to predict the prognosis of cancer patients. However, the impact of immune responses and tumor escape on patient prognosis in human cancer is poorly understood. Methods: We analyzed large retrospective cohorts of colorectal cancer patients. Results: We showed that tumors from human colorectal cancer with a high density of infiltrating memory and effector memory T-cells (T-EM) are less likely to disseminate to lymphovascular and perineural structures and to regional lymph-nodes (New Engl J Med, 2005). We showed that the combination of immune parameters associating the nature, the density, the functional orientation and the location of immune cells within the tumor was essential to accurately define the impact of the local host immune reaction on patients prognosis (Science, 2006). We proposed to define these immune criteria as “immune contexture.” Analysis of patients with early-stage colorectal cancer confirmed the major role of cyotoxic effector T cells in predicting the prognosis of the patients (J Clin Oncol, 2009). Investigation of the primary tumor microenvironment allowed us to uncover the association of favorable outcomes with efficient coordination of the intratumoral immune response. We described four major immune coordination profiles within primary tumors depending on the balance between tumor escape and immune coordination. Recent advances analyzing mechanisms responsible for lymphocytic infiltration will be discussed. Conclusions: The density and the immune-cell location within the tumor have a prognostic value that is superior of those of the TNM classifications. Tumor invasion is statistically dependent on the host-immune reaction. No significant financial relationships to disclose.

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