How can senescent cells, which are damaged and growth arrested, both block tumor initiation as well as fuel its growth? A recent study published online @CD_AACR from @linzhou0515 in the lab uncovered some new insights into this puzzle. https://t.co/wajd5q8Wio

@UMassChan @linzhou0515 @peura_jessica @PitarresiLab @artmercurio @HarmonyTurk @CR_AACR With her F31 fellowship, @katcmurph is now using these models to explore the molecular and cellular determinants of immune suppression and immunotherapy failure in another aggressive and highly metastatic form of CRPC: neuroendocrine prostate cancer. Stay tuned for more to come!

@UMassChan @linzhou0515 @peura_jessica @PitarresiLab @artmercurio It was great working with Executive Editor @HarmonyTurk @CR_AACR, who made the publishing process streamlined and timely. Thanks also to our Reviewers for their helpful comments and suggestions that improved the manuscript.

This was a great team effort from many people in our lab and great colleagues @UMassChan: @linzhou0515 @peura_jessica @PitarresiLab @artmercurio

Given the number of bispecific antibodies targeting VEGFR2/PD-L1 currently on the market and in clinical trials, we believe that the 8-9% of CRPC patients harboring MYC and p53 genetic alterations could highly benefit from these immunotherapies as a “precision medicine” approach.

Moreover, VEGFR2 blockade could potentiate anti-PD-L1 immune checkpoint blockade therapy that is generally ineffective in the broader prostate cancer patient population in our MYC and p53 altered CRPC models.

Treatment with VEGFR2 blocking antibodies could reactivate cytotoxic anti-tumor T cell immunity to block prostate tumor growth and metastasis in this aggressive MYC and p53-driven genetic CRPC subtype.

Mechanistically, MYC and p53 alterations cooperated to drive VEGF secretion from prostate tumor cells. Though VEGF typically mediates vascular remodeling, Kat found that VEGF could also directly reduce migration and activation of CD8+ T cells expressing its receptor, VEGFR2.

She identified a genetic subtype of castration-resistant prostate cancer (CRPC) with MYC oncogene overexpression and p53 tumor suppressor deletion that had reduced NK and T cell infiltration and activity compared to other subtypes and an overall dismal prognosis in mice and men.

Using an in vivo electroporation technique that allows for generation of any genetic alteration found in human cancers in mice, Kat produced a suite of prostate cancer mouse models with different oncogene and tumor suppressor alterations and analyzed their immune landscapes.

Do acquired mutations that drive tumorigenesis also contribute to immune evasion that promotes progression and therapy resistance? In a recent study published online @CR_AACR, @katcmurph created new mouse models of prostate cancer to address this question. https://t.co/fFmoTxACJq

A nice write-up on @katcmurph's F31 Fellowship award and her ongoing research investigating genetic determinants of prostate cancer immune suppression! Also be sure to checkout her study recently published in @CR_AACR. https://t.co/fFmoTxACJq

@CD_AACR @linzhou0515 @katcmurph @BinLiu49077152 @KahindeG @BoyangMa1218 @Nikita2106 @ChaitanyaParik @PitarresiLab @linzhou0515, the 1st author who drove the study, is currently on the job market. She is following up on this work to investigate how p21+ stromal cells arise, how they are different from other senescent cells, and how to best target them. Snatch her up before someone else does!

@CD_AACR @linzhou0515 @katcmurph @BinLiu49077152 @KahindeG @BoyangMa1218 @Nikita2106 @ChaitanyaParik @PitarresiLab As always, it was a real pleasure working with Michele Hartsough and the editorial team @CD_AACR. And thanks to our Reviewers for their helpful comments along the way that improved the manuscript.

@CD_AACR @linzhou0515 This was an amazing team effort from all authors, including my former Ph.D. mentor! To highlight those online: @katcmurph @BinLiu49077152 @KahindeG @BoyangMa1218 @Nikita2106 @ChaitanyaParik @PitarresiLab

@CD_AACR @linzhou0515 Our findings suggest that, in contrast to senescent transformed epithelial cells that are growth arrested and tumor suppressive, p21+ senescent stromal cells secrete a SASP the fuels immune suppression and tumor growth that can be targeted for prostate cancer immunotherapy.

@CD_AACR @linzhou0515 Targeting p21+ senescent stromal cells genetically or through treatment with ABT-263 could also enhance anti-PD-1 immune checkpoint blockade therapy outcomes in advanced, castration-resistant prostate cancer models.

@CD_AACR @linzhou0515 Administration of the senolytic BCL-2 family inhibitor ABT-263 also preferentially targeted p21+ senescent stromal cells, leading to reactivation of anti-tumor T cell immunity that could even block prostate tumor initiation.

@CD_AACR @linzhou0515 Through a series experiments to deplete p16+ or p21+ cells in different cell compartments in mice, we found that while p16 removal had no effect on tumor progression, p21+ stromal cell depletion could block the SASP to reverse myeloid immune suppression and delay tumor growth.

@CD_AACR @linzhou0515 Whereas p16+ senescent epithelial cells had very low expression of inflammatory factors through the senescence-associated secretory phenotype (SASP), p21+ senescent stromal cells had high production of SASP cytokines that recruit suppressive myeloid cells.

@CD_AACR @linzhou0515 To our surprise, single cell analysis revealed that different senescent cell populations expressed different senescent markers. While transformed senescent epithelial preferentially expressed p16, stromal senescent cells expressed another putative senescence marker: p21.