The Tumor Microenvironment and Immunotherapy in Prostate and Bladder Cancer

Nair, Sujit S.; Weil, Rachel; Dovey, Zachary; Davis, Avery; Tewari, Ashutosh

doi:10.1016/j.ucl.2020.10.005

Cited by 58 publications

(37 citation statements)

References 269 publications

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“…The immunologic classification of tumors as “hot” or “cold” is determined by parameters that include the presence of specific tumor-infiltrating lymphocytes (TILs) such as CD4 + and CD8 + T cells, high TMB, as well as expression and recognition of neoantigens via MHC molecules by APCs. “Hot” tumors trigger an antitumor immune response based on these factors [ 9 ]. Conversely, “cold” tumors have been shown to have low TILs, impaired APC activation and presence of immune-suppressive cell types.…”

Section: Immune Resistance Mechanisms In Prostate Cancermentioning

confidence: 99%

“…Conversely, "cold" tumors have been shown to have low TILs, impaired APC activation and presence of immune-suppressive cell types. PCa falls within the category of a "cold" tumor [9,17].…”

Section: Immune Resistance Mechanisms In Prostate Cancermentioning

confidence: 99%

“…The mechanisms through which PCa evades the immune system, maintains the "cold" TME and mediates immunosuppression continues to be elucidated. In order to best overcome the resistance to immunotherapies in the setting of advanced PCa, it is critical to understand the mechanisms that lead to immune resistance in the context of the cellular components of the TME that potentiate immunosuppression and the molecules and genetic pathways that facilitate continued tumor growth [9]. Some of these key immune resistance mechanisms that will be explored include altered MHC molecule expression, decreased TMB, loss of tumor suppressor proteins, abberant androgen receptor signaling as well as increased infiltration of immune-suppressive cell types (i.e., T-regulatory cells, myeloid-derived suppressor cells) in the TME [9,17,18].…”

Section: Immune Resistance Mechanisms In Prostate Cancermentioning

confidence: 99%

“…To date, however, patients with advanced PCa have not yet benefited to the same extent as those with more “immunologically hot” or “responsive” tumors such as melanoma, lung cancer, renal cell carcinoma or urothelial carcinoma [ 3 , 6 , 7 ]. In fact, PCa has been classified as a “cold tumor” with minimal response to immune-related treatment modalities [ 8 , 9 , 10 ]. Low tumor-associated antigen expression, decreased major histocompatibility complex (MHC) presentation of tumor antigens, tumor suppressor and DNA repair enzyme defects, and poor immune-modulating signaling are some key processes that have a role in this complex tumor environment, altering the overall anti-tumor response [ 8 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Overcoming Immune Resistance in Prostate Cancer: Challenges and Advances

Movassaghi

Chung

Anderson

et al. 2021

Cancers

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The use of immunotherapy has become a critical treatment modality in many advanced cancers. However, immunotherapy in prostate cancer has not been met with similar success. Multiple interrelated mechanisms, such as low tumor mutational burden, immunosuppressive cells, and impaired cellular immunity, appear to subvert the immune system, creating an immunosuppressive tumor microenvironment and leading to lower treatment efficacy in advanced prostate cancer. The lethality of metastatic castrate-resistant prostate cancer is driven by the lack of therapeutic regimens capable of generating durable responses. Multiple strategies are currently being tested to overcome immune resistance including combining various classes of treatment modalities. Several completed and ongoing trials have shown that combining vaccines or checkpoint inhibitors with hormonal therapy, radiotherapy, antibody–drug conjugates, chimeric antigen receptor T cell therapy, or chemotherapy may enhance immune responses and induce long-lasting clinical responses without significant toxicity. Here, we review the current state of immunotherapy for prostate cancer, as well as tumor-specific mechanisms underlying therapeutic resistance, with a comprehensive look at the current preclinical and clinical immunotherapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and impaired cellular immunity that have largely limited the utility of immunotherapy in advanced prostate cancer.

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Section: Immune Resistance Mechanisms In Prostate Cancermentioning

confidence: 99%

“…Conversely, "cold" tumors have been shown to have low TILs, impaired APC activation and presence of immune-suppressive cell types. PCa falls within the category of a "cold" tumor [9,17].…”

Section: Immune Resistance Mechanisms In Prostate Cancermentioning

confidence: 99%

Section: Immune Resistance Mechanisms In Prostate Cancermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Overcoming Immune Resistance in Prostate Cancer: Challenges and Advances

Movassaghi

Chung

Anderson

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…Recent animal studies have demonstrated promise when combining RT with locally delivered anti-CD40 even for immunologically cold tumors like pancreatic cancer ( 8 , 9 ). The approach has potential to be effective across different tumor types, since the neoantigens generated in vivo by RT are tumor/patient specific, and the anti-CD40 can act on APCs present in the tumor microenvironment without the need for the tumor to express CD40 as with invasive prostate cancer ( 3 , 10 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

Optimizing In Situ Vaccination During Radiotherapy

et al. 2021

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Effective in situ cancer vaccines require both a means of tumor cell death and a source of adjuvant to activate local dendritic cells. Studies have shown that the use of radiotherapy (RT) to induce tumor cell death and anti-CD40 to activate dendritic cells can result in in situ vaccination in animal models. Here, investigations are carried out on potential strategies to enhance such in situ vaccination. Strategies investigated include the use of smart immunogenic biomaterials (IBM) loaded with anti-CD40 in different tumor types including immunologically cold tumors like pancreatic and prostate tumors. The use of downstream checkpoint inhibitors to further boost such in situ vaccination is also examined. Results indicate that the use of IBM to deliver the anti-CD40 significantly enhances the effectiveness of in situ vaccination with anti-CD40 compared with direct injection in pancreatic and prostate cancers (p < 0.001 and p < 0.0001, respectively). This finding is consistent with significant increase in infiltration of antigen-presenting cells in the treated tumor, and significant increase in the infiltration of CD8+ cytotoxic T lymphocyte into distant untreated tumors. Moreover, in situ vaccination with IBM is consistently observed across different tumor types. Meanwhile, the addition of downstream immune checkpoint inhibitors further enhances overall survival when using the IBM approach. Overall, the findings highlight potential avenues for enhancing in situ vaccination when combining radiotherapy with anti-CD40.

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Immunotherapy in the Treatment of Localized Genitourinary Cancers

et al. 2023

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ImportanceA true revolution in the management of advanced genitourinary cancers has occurred with the discovery and adoption of immunotherapy (IO). The therapeutic benefits of IO were recently observed not to be solely confined to patients with disseminated disease but also in select patients with localized and locally advanced genitourinary neoplasms.ObservationsKEYNOTE-057 demonstrated the benefit of pembrolizumab monotherapy for treating high-risk nonmuscle invasive bladder cancer unresponsive to bacillus Calmette-Guérin (BCG), resulting in recent US Food and Drug Administration approval. Furthermore, a current phase 3 trial (Checkmate274) demonstrated a disease-free survival benefit with the administration of adjuvant nivolumab vs placebo in muscle-invasive urothelial carcinoma after radical cystectomy. In addition, the recent highly publicized phase 3 KEYNOTE 564 trial demonstrated a recurrence-free survival benefit of adjuvant pembrolizumab in patients with high-risk localized/locally advanced kidney cancer.Conclusions and RelevanceThe adoption and integration of IO in the management of localized genitourinary cancers exhibiting aggressive phenotypes are becoming an emerging therapeutic paradigm. Clinical oncologists and scientists should become familiar with these trials and indications because they are likely to dramatically change our treatment strategies in the months and years to come.

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The Tumor Microenvironment and Immunotherapy in Prostate and Bladder Cancer

Cited by 58 publications

References 269 publications

Overcoming Immune Resistance in Prostate Cancer: Challenges and Advances

Overcoming Immune Resistance in Prostate Cancer: Challenges and Advances

Optimizing In Situ Vaccination During Radiotherapy

Immunotherapy in the Treatment of Localized Genitourinary Cancers

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