Sphere-derived Prostate Cancer Stem Cells Are Resistant to γδ T Cell Cytotoxicity

Abstract

Background/Aim: γδ T cells mediate cytotoxicity against prostate cancer (PCa) cells in vitro; however, the clinical efficacy of γδ T cell-targeted immunotherapy for recurrent and metastatic PCa is unsatisfactory. We hypothesized that the resistance of recurrent and metastatic PCa to γδ T cells is related to the presence of prostate cancer stem cells (PCSCs), and we examined their relationship. Materials and Methods: PCa spheres (prostaspheres) were generated from five PCa cell lines, and their susceptibility to cytotoxicity by γδ T cells was investigated. Expression of stemness-related markers was evaluated by qRT-PCR. Results: Prostasphere-derived cancer cells were resistant to lysis by γδ T cells and expressed higher levels of several stemness markers, including CD133, NANOG, SOX2, and OCT4, than the parental PCa cell lines. Conclusion: Ex vivo-expanded γδ T cells are not effective against PCSCs.

Low Levels of TRIM28-Interacting KRAB-ZNF Genes Associate with Cancer Stemness and Predict Poor Prognosis of Kidney Renal Clear Cell Carcinoma Patients

“…Recent in vitro studies suggest that the cancer stem cell population exhibits strong resistance to γδ T cell-mediated killing. However, further experimental confirmation is needed to prove this phenomenon in vivo [ 65 ].…”

Strategies to Improve the Antitumor Effect of γδ T Cell Immunotherapy for Clinical Application

“…Previously, we generated prostate cancer spheres and used them to examine the cytotoxicity of ex vivo-expanded γδ T cells against sphere-derived prostate cancer cells. Sphere-derived prostate cancer cells were resistant to ex vivo-expanded γδ T cells; in addition, their stem cell markers, including CD133, NANOG, SOX2, and OCT4, were upregulating compared with those of parental cells [129]. These results suggest that ex vivo-expanded γδ T cells will not be effective against CSCs.…”

Understanding and targeting prostate cancer cell heterogeneity and plasticity

“…PCSCs, in spite of phenotypic diversity, are commonly endowed with high clonogenic and tumor-initiating/tumor-propagating activities. Importantly, PCSCs have been reported to be intrinsically therapy-resistant, including resistance to castration, chemotherapy, radiotherapy and, likely, immunotherapy [ 2 , 3 , 125 , 131 , 138 , 218 , 226 , 227 , 251 – 253 , 265 , 278 , 299 , 300 , 310 , 313 , 315 ]. For example, the PSA −/lo PCa cells are resistant to castration, antiandrogens, prooxidants and chemodrugs [ 131 , 144 ] and ABCG2 + PCSCs are resistant to ARSIs due to increased efflux of androgens [ 218 ].…”

“…Similarly, the PSA −/lo /MHC −-/l o PCSCs are resistant to docetaxel as a result of enhanced Notch and Hedgehog signaling [ 226 ], and the CD4 4 + [ 299 ], LP-like [ 227 , 252 ] and hypoxia-induced [ 265 ] PCSCs are all inherently castration- and chemo-resistant. Finally, sphere-derived PCSCs are resistant toγ?d T cell-mediated cytotoxicity [ 300 ] and PCSCs, like many other CSCs, are generally ‘immuno-deficient’ lacking the expression of many immunogenic molecules [ 160 ].…”

“…Therefore, PCSCs may not be very susceptible to immune-mediated cell killing [ 160 ]. For example, PCSCs have been shown to be refractory to γδ T cell-mediated cytotoxicity [ 300 ]. On the other hand, a recent phase I/II clinical trial hints that vaccination in PCa patients against RhoC could elicit long-lasting immune response [ 305 ].…”