More Like this

1. Impact of Neoantigen Expression and T-Cell Activation on Breast Cancer Survival

   https://doi.org/10.3390/cancers13122879  

   Li, Wenjing ; Amei, Amei ; Bui, Francis ; Norouzifar, Saba ; Lu, Lingeng ; Wang, Zuoheng ( June 2021 , Cancers)

   Neoantigens are derived from tumor-specific somatic mutations. Neoantigen-based synthesized peptides have been under clinical investigation to boost cancer immunotherapy efficacy. The promising results prompt us to further elucidate the effect of neoantigen expression on patient survival in breast cancer. We applied Kaplan–Meier survival and multivariable Cox regression models to evaluate the effect of neoantigen expression and its interaction with T-cell activation on overall survival in a cohort of 729 breast cancer patients. Pearson’s chi-squared tests were used to assess the relationships between neoantigen expression and clinical pathological variables. Spearman correlation analysis was conducted to identify correlations between neoantigen expression, mutation load, and DNA repair gene expression. ERCC1, XPA, and XPC were negatively associated with neoantigen expression, while BLM, BRCA2, MSH2, XRCC2, RAD51, CHEK1, and CHEK2 were positively associated with neoantigen expression. Based on the multivariable Cox proportional hazard model, patients with a high level of neoantigen expression and activated T-cell status showed improved overall survival. Similarly, in the T-cell exhaustion and progesterone receptor (PR) positive subgroups, patients with a high level of neoantigen expression showed prolonged survival. In contrast, there was no significant difference in the T-cell activation and PR negative subgroups. In conclusion, neoantigens may serve as immunogenic agents for immunotherapy in breast cancer. 

   more » « less
2. Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer

   https://doi.org/10.1002/pros.24123  

   Ledet, Elisa M. ; Burgess, Earle F. ; Sokolova, Alexandra O. ; Jaeger, Ellen B. ; Hatton, Whitley ; Moses, Marcus ; Miller, Patrick ; Cotogno, Patrick ; Layton, Jodi ; Barata, Pedro ; et al ( April 2021 , The Prostate)

   The goal of this study is to evaluate germline genetic variants in African American men with metastatic prostate cancer as compared to those in Caucasian men with metastatic prostate cancer in an effort to understand the role of genetic factors in these populations.

   African American and Caucasian men with metastatic prostate cancer who had germline testing using multigene panels were used to generate comparisons. Germline genetic results, clinical parameters, and family histories between the two populations were analyzed.

   A total of 867 patients were included in this retrospective study, including 188 African American and 669 Caucasian patients. There was no significant difference in the likelihood of a pathogenic or likely‐pathogenic variants (PV/LPVs) between African American and Caucasian patients (p = .09). African American patients were more likely to have a variant of unknown significance than Caucasians (odds ratio [OR] = 1.95;p < .0001). BRCA1 PV/LPVs were higher in African Americans (OR = 4.86;p = .04). African American patients were less likely to have a PV/LPV in non‐BRCA DNA repair genes (OR = 0.30;p = .008). Family history of breast (OR = 2.09;p = .002) or ovarian cancer (OR = 2.33;p = .04) predicted PV/LPVs in Caucasians but not African‐Americans. This underscores the limitations of family history in AA men and the importance of personal history to guide germline testing in AA men.

   In metastatic prostate cancer patients, PV/LPVs of tested genes did not vary by race, BRCA1 PV/LPVs were more common in the African American subset. However, PV/LPVs in non‐BRCA DNA repair genes were less likely to be encountered in African Americans. Family history associated with genetic testing results in Caucasians only.

    

   more » « less
3. Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators

   https://doi.org/10.1136/jitc-2020-001819  

   Hou, Jiakai ; Wang, Yunfei ; Shi, Leilei ; Chen, Yuan ; Xu, Chunyu ; Saeedi, Arash ; Pan, Ke ; Bohat, Ritu ; Egan, Nicholas A. ; McKenzie, Jodi A. ; et al ( February 2021 , Journal for ImmunoTherapy of Cancer)

   null (Ed.)

   Background Despite approval of immunotherapy for a wide range of cancers, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conventional methods to systematically evaluate the potential of tumor intrinsic factors to act as immune regulators in patients with cancer. Methods To identify immunosuppressive mechanisms in non-responders to cancer immunotherapy in an unbiased manner, we performed genome-wide CRISPR immune screens and integrated our results with multi-omics clinical data to evaluate the role of tumor intrinsic factors in regulating two rate-limiting steps of cancer immunotherapy, namely, T cell tumor infiltration and T cell-mediated tumor killing. Results Our studies revealed two distinct types of immune resistance regulators and demonstrated their potential as therapeutic targets to improve the efficacy of immunotherapy. Among them, PRMT1 and RIPK1 were identified as a dual immune resistance regulator and a cytotoxicity resistance regulator, respectively. Although the magnitude varied between different types of immunotherapy, genetically targeting PRMT1 and RIPK1 sensitized tumors to T-cell killing and anti-PD-1/OX40 treatment. Interestingly, a RIPK1-specific inhibitor enhanced the antitumor activity of T cell-based and anti-OX40 therapy, despite limited impact on T cell tumor infiltration. Conclusions Collectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations. 

   more » « less
4. Molecular assessment of pretransplant chemotherapy in the treatment of juvenile myelomonocytic leukemia

   https://doi.org/10.1002/pbc.27948  

   Hecht, Anna ; Meyer, Julia ; Chehab, Farid F. ; White, Kristie L. ; Magruder, Kevin ; Dvorak, Christopher C. ; Loh, Mignon L. ; Stieglitz, Elliot ( July 2019 , Pediatric Blood & Cancer)

   Despite the intensity of hematopoietic stem cell transplantation (HCT), relapse remains the most common cause of death in juvenile myelomonocytic leukemia (JMML). In contrast to other leukemias where therapy is used to reduce leukemic burden prior to transplant, many patients with JMML proceed directly to HCT with active disease. The objective of this study was to elucidate whether pre‐HCT therapy has an effect on the molecular burden of disease and how this affects outcome post‐HCT.

   Twenty‐one patients with JMML who received pre‐HCT therapy and were transplanted at UCSF were analyzed in this study. The mutant allele frequency of the driver mutation was assessed before and after pre‐HCT therapy, using custom amplicon next‐generation sequencing.

   Of the 21 patients, seven patients (33%) responded to therapy with a significant reduction in their mutant allele frequency and were classified as molecular responders. Six of these patients received moderate‐intensity chemotherapy, one patient received only azacitidine. The 5‐year progression‐free survival after HCT of molecular responders was 100% versus 61% for nonresponders (P = .12). Survival of molecular nonresponders was not improved by use of high‐intensity conditioning, but patients were salvaged if they experienced severe graft versus host disease. There were no baseline clinical characteristics that were associated with response to pre‐HCT therapy.

   Despite the myelodysplastic nature of JMML, patients treated with pre‐HCT therapy can achieve molecular remissions. These patients experienced a trend toward improved outcomes post‐HCT. Importantly, molecular testing can be helpful to distinguish between responders and nonresponders and should become an integral part of clinical care.

    

   more » « less
5. Exploring Gut Microbiome in Predicting the Efficacy of Immunotherapy in Non-Small Cell Lung Cancer

   https://doi.org/10.3390/cancers14215401  

   Liu, Ben ; Chau, Justin ; Dai, Qun ; Zhong, Cuncong ; Zhang, Jun ( November 2022 , Cancers)

   We performed various analyses on the taxonomic and functional features of the gut microbiome from NSCLC patients treated with immunotherapy to establish a model that may predict whether a patient will benefit from immunotherapy. We collected 65 published whole metagenome shotgun sequencing samples along with 14 samples from our previous study. We systematically studied the taxonomical characteristics of the dataset and used both the random forest (RF) and the multilayer perceptron (MLP) neural network models to predict patients with progression-free survival (PFS) above 6 months versus those below 3 months. Our results showed that the RF classifier achieved the highest F-score (85.2%) and the area under the receiver operating characteristic curve (AUC) (95%) using the protein families (Pfam) profile, and the MLP neural network classifier achieved a 99.9% F-score and 100% AUC using the same Pfam profile. When applying the model trained in the Pfam profile directly to predict the treatment response, we found that both trained RF and MLP classifiers significantly outperformed the stochastic predictor in F-score. Our results suggested that such a predictive model based on functional (e.g., Pfam) rather than taxonomic profile might be clinically useful to predict whether an NSCLC patient will benefit from immunotherapy, as both the F-score and AUC of functional profile outperform that of taxonomic profile. In addition, our model suggested that interactive biological processes such as methanogenesis, one-carbon, and amino acid metabolism might be important in regulating the immunotherapy response that warrants further investigation. 

   more » « less