Immune Checkpoint B7-H3 is a Therapeutic Vulnerability in Prostate Cancer Harboring PTEN and TP53 Deficiencies - Di Zhao
June 5, 2023
Andrea Miyahira invites Di Zhao to discuss her research published in Science Translational Medicine entitled “Immune checkpoint B7-H3 is a therapeutic vulnerability in prostate cancer harboring PTEN and TP53 deficiencies.” Dr. Zhao's team explored immune checkpoint B7-H3, identified as a promising target for advanced prostate cancer with PTEN and p53 deficiencies. Their analysis of immune checkpoint molecules revealed B7-H3 overexpression linked to these defects. Laboratory trials showed that B7-H3 depletion slowed tumor progression and increased T-cell and NK cell infiltration. However, B7-H3 inhibition also elevated PD-L1 expression and regulatory T-cell infiltration, potentially impairing B7-H3 inhibitors' antitumor effects. Notably, dual blockade of B7-H3 with CTLA-4 exhibited promising results, inhibiting tumor growth and extending survival in mouse models. Future research will investigate B7-H3 expression in different molecular subtypes and potential clinical applications of these findings.
Biographies:
Di Zhao, PhD, The University of Texas, MD Anderson Cancer Center, Houston, Texas
Andrea K Miyahira, PhD, Director of Global Research & Scientific Communications, The Prostate Cancer Foundation
Biographies:
Di Zhao, PhD, The University of Texas, MD Anderson Cancer Center, Houston, Texas
Andrea K Miyahira, PhD, Director of Global Research & Scientific Communications, The Prostate Cancer Foundation
Read the Full Video Transcript
Andrea Miyahira: Hi everyone. I'm Andrea Miyahira, the Senior Director of Global Research and Scientific Communications at the Prostate Cancer Foundation. Joining me today is Dr. Di Zhao, an Assistant Professor at MD Anderson Cancer Center. Dr. Zhao and team recently published a paper, Immune Checkpoint B7-H3 is a Therapeutic Vulnerability in Prostate Cancer Harboring PTEN and p53 Deficiencies in Science Translational Medicine. Dr. Zhao, I look forward to learning about your study.
Di Zhao: Thank you so much, Andrea, for this great opportunity to present our studies recently published in Science Translational Medicine. Immunotherapy targeting PD-1 or CTLA-4 has achieved significnt results in some cancer types. However, prostate cancer showed an overall resistance to those therapies and the genetic alterations of the tumor suppressor genes PTEN and p53 are very common in advance prostate cancer and are associated with disease progression and metastasis, and also worse outcomes. To identify the novel immunotherapy target in PTEN/p53-deficient prostate cancer, we performed a gene expression pattern analysis of 53 immune checkpoint molecules in a human prostate cancer dataset.
We found that the B7-H3 ranked as the top number one genes associated with both PTEN and p53 defects. Both in genetic engineered mouse models and human prostate cancer cell lines, code deletions of the PTEN and p53 caused the B7-H3 overexpression. The mechanism takeaway, we found that SP1 serves as transcriptional factor of B7-H3 and they mediated B7-H3 overexpression in the prostate tumors with PTEN and p53 defects.
Next, we tried to understand the biological function of B7-H3 in prostate tumors in this context. In knockout B7-H3 in syngeneic prostate cancer mouse cell lines, we found that the B7-H3 depletion in prostate cancer cells can significantly inhibit the tumor progression and meanwhile increase the infiltration of T cells and the NK cells in the tumor environment. Next, we generate a novel genetic engineered mouse model and showed that the prostate-specific B7-H3 depletion can delay the progression of PTEN/p53-deficient prostate tumors, and also prolong the overall survival of the mice.
Next, we tested the effects of the B7-H3 monoclonal antibody inhibitor in our preclinical models of PTEN/p53-deficient CRPC, castration-resistant prostate cancer. In combination with AR inhibitor enzalutamide, we found the B7-H3 inhibition showed the antitumor effects, and meanwhile increased the infiltration of T cells and the NK cells in prostate tumor. However, to our surprise, the B7-H3 inhibition also caused the increase of the PD-L1 expression in myeloid cells and also increased the infiltration of regulatory T-cells in the tumor microenvironment. We hypothesize that these effects may serve as a commendatory immunosuppressive mechanism, which hinder the antitumor effects of the B7-H3 inhibitor.
Next, we tried to combine the B7-H3 inhibitor with a blockade of the PD-1, PD-L1, or CTLA-4. As shown here, we found that dual blockade of B7-H3 with CTLA-4 can achieve durable antitumor effects in castration-resistant prostate cancer mouse models. Those combinations significantly intubated tumor growth and prolonged the oral survivals of the mice, and also protect the mice from the re-challenge of secondary tumors.
In conclusion, our studies demonstrated that B7-H3 is a promising immunotherapy target in advance the prostate cancer containing the PTEN and p53 defects. We also found that B7-H3 is overexpressed in PTEN/p53-deficient prostate tumors and also contributes to immunosuppression and the tumor progression. Meanwhile, we also demonstrated that the B7-H3 inhibition may cause the elevation of the PD-1 or PD-L1 axis and increasing the regulatory T-cells in the tumor microenvironment. And those commendatory effects may hinder the effects of B7-H3 inhibition in vivo. At last, we showed that dual blockade of B7-H3 with PD-LA always CTLA-4 can achieve durable antitumor effects in PTEN/p53-deficient CRPC models.
In the past a decade, many approaches have been developed to targeting B7-H3, and some of them are currently tested in clinical trials. Our studies provided new insights into the biomarker-driven combinatorial immunotherapy targeting B7-H3 in advanced prostate cancer, among other malignancies. Please find more details in our paper. At last, I would like to thank all the members, our collaborators, and also our founding support from the NCI, CPRIT, and the Prostate Cancer Foundation. Thank you so much for you attention.
Andrea Miyahira: Thank you, Dr. Zhao, for sharing this. Have you evaluated B7-H3 expression in tumor samples from patients with other molecular subtypes of CRPC, for instance, neuroendocrine prostate cancer and/or other stages of prostate cancer?
Di Zhao: Sure, that's a great question. Now we are collaborating with a GU oncologist, Dr. Ana Aparicio, to test the expression pattern of B7-H3 in more than 100 cases of human samples of mCRPC. We will use a digital spatial profiling, combined with the multiple MHC approach to determine the B7-H3 expression in cancer cells and also in the tumor microenvironment. We aim to determine B7-H3 expression and association with the different molecular subtypes, and also the AVPC signature genes including PTEN, p53, and RB1. So I think in a near future we will have a good answer for you.
Andrea Miyahira: Thank you. Other studies have suggested that AR also regulates B7-H3 expression. You guys investigated the roles for AR versus SP1?
Di Zhao: Yeah. Yes, that's something we are doing now, actually. Previously Dr. de Bono's lab and also Dr. Lawton's lab, both of them reported an impact of the AR signaling on the B7-H3 expression. So we definitely want to know whether SP1 is involved in this process or not, and how this AR signaling crosstalk with the PTEN/p53 pathway in regulating B three expression in the context of the prostate cancer and the CRPC.
Andrea Miyahira: Thank you. Finally, what are your next steps and what are the steps that you guys are looking at for translating these findings into the clinic?
Di Zhao: Sure. We definitely want to do that for next step. And so, as I mentioned, many approaches has been developed to target B7-H3 and some of them are in clinical trials. So, next step, for a preclinical part, we want to determine whether the combination strategies identified in this study can also apply to other B7-H3 targeted therapies, like a B7-H3 ADC and also a CAR T and bispecific antibodies, something like that. Also, we want to know whether the deficiencies of the PTEN and p53 tumor suppressor genes may synthesize the prostate tumors to this B7-H3-targeted therapy. Also, will collaborate with Dr. Ana Aparicio to run co-clinical trials for some of those regions once we see the promising results from our preclinical model.
Andrea Miyahira: Okay. Well this is so wonderful. Thank you so much for joining me today, Dr. Zhao.
Di Zhao: Thank you so much, Andrea, for inviting me to give you this presentation and the opportunity to introduce our studies. Most importantly, I want to thank Prostate Cancer Foundation to continuously support our research since 2017, and also support myself and my team to do this fantastic research. Yeah, I hope we will have some good translational studies come out in the next few years.
Andrea Miyahira: Hi everyone. I'm Andrea Miyahira, the Senior Director of Global Research and Scientific Communications at the Prostate Cancer Foundation. Joining me today is Dr. Di Zhao, an Assistant Professor at MD Anderson Cancer Center. Dr. Zhao and team recently published a paper, Immune Checkpoint B7-H3 is a Therapeutic Vulnerability in Prostate Cancer Harboring PTEN and p53 Deficiencies in Science Translational Medicine. Dr. Zhao, I look forward to learning about your study.
Di Zhao: Thank you so much, Andrea, for this great opportunity to present our studies recently published in Science Translational Medicine. Immunotherapy targeting PD-1 or CTLA-4 has achieved significnt results in some cancer types. However, prostate cancer showed an overall resistance to those therapies and the genetic alterations of the tumor suppressor genes PTEN and p53 are very common in advance prostate cancer and are associated with disease progression and metastasis, and also worse outcomes. To identify the novel immunotherapy target in PTEN/p53-deficient prostate cancer, we performed a gene expression pattern analysis of 53 immune checkpoint molecules in a human prostate cancer dataset.
We found that the B7-H3 ranked as the top number one genes associated with both PTEN and p53 defects. Both in genetic engineered mouse models and human prostate cancer cell lines, code deletions of the PTEN and p53 caused the B7-H3 overexpression. The mechanism takeaway, we found that SP1 serves as transcriptional factor of B7-H3 and they mediated B7-H3 overexpression in the prostate tumors with PTEN and p53 defects.
Next, we tried to understand the biological function of B7-H3 in prostate tumors in this context. In knockout B7-H3 in syngeneic prostate cancer mouse cell lines, we found that the B7-H3 depletion in prostate cancer cells can significantly inhibit the tumor progression and meanwhile increase the infiltration of T cells and the NK cells in the tumor environment. Next, we generate a novel genetic engineered mouse model and showed that the prostate-specific B7-H3 depletion can delay the progression of PTEN/p53-deficient prostate tumors, and also prolong the overall survival of the mice.
Next, we tested the effects of the B7-H3 monoclonal antibody inhibitor in our preclinical models of PTEN/p53-deficient CRPC, castration-resistant prostate cancer. In combination with AR inhibitor enzalutamide, we found the B7-H3 inhibition showed the antitumor effects, and meanwhile increased the infiltration of T cells and the NK cells in prostate tumor. However, to our surprise, the B7-H3 inhibition also caused the increase of the PD-L1 expression in myeloid cells and also increased the infiltration of regulatory T-cells in the tumor microenvironment. We hypothesize that these effects may serve as a commendatory immunosuppressive mechanism, which hinder the antitumor effects of the B7-H3 inhibitor.
Next, we tried to combine the B7-H3 inhibitor with a blockade of the PD-1, PD-L1, or CTLA-4. As shown here, we found that dual blockade of B7-H3 with CTLA-4 can achieve durable antitumor effects in castration-resistant prostate cancer mouse models. Those combinations significantly intubated tumor growth and prolonged the oral survivals of the mice, and also protect the mice from the re-challenge of secondary tumors.
In conclusion, our studies demonstrated that B7-H3 is a promising immunotherapy target in advance the prostate cancer containing the PTEN and p53 defects. We also found that B7-H3 is overexpressed in PTEN/p53-deficient prostate tumors and also contributes to immunosuppression and the tumor progression. Meanwhile, we also demonstrated that the B7-H3 inhibition may cause the elevation of the PD-1 or PD-L1 axis and increasing the regulatory T-cells in the tumor microenvironment. And those commendatory effects may hinder the effects of B7-H3 inhibition in vivo. At last, we showed that dual blockade of B7-H3 with PD-LA always CTLA-4 can achieve durable antitumor effects in PTEN/p53-deficient CRPC models.
In the past a decade, many approaches have been developed to targeting B7-H3, and some of them are currently tested in clinical trials. Our studies provided new insights into the biomarker-driven combinatorial immunotherapy targeting B7-H3 in advanced prostate cancer, among other malignancies. Please find more details in our paper. At last, I would like to thank all the members, our collaborators, and also our founding support from the NCI, CPRIT, and the Prostate Cancer Foundation. Thank you so much for you attention.
Andrea Miyahira: Thank you, Dr. Zhao, for sharing this. Have you evaluated B7-H3 expression in tumor samples from patients with other molecular subtypes of CRPC, for instance, neuroendocrine prostate cancer and/or other stages of prostate cancer?
Di Zhao: Sure, that's a great question. Now we are collaborating with a GU oncologist, Dr. Ana Aparicio, to test the expression pattern of B7-H3 in more than 100 cases of human samples of mCRPC. We will use a digital spatial profiling, combined with the multiple MHC approach to determine the B7-H3 expression in cancer cells and also in the tumor microenvironment. We aim to determine B7-H3 expression and association with the different molecular subtypes, and also the AVPC signature genes including PTEN, p53, and RB1. So I think in a near future we will have a good answer for you.
Andrea Miyahira: Thank you. Other studies have suggested that AR also regulates B7-H3 expression. You guys investigated the roles for AR versus SP1?
Di Zhao: Yeah. Yes, that's something we are doing now, actually. Previously Dr. de Bono's lab and also Dr. Lawton's lab, both of them reported an impact of the AR signaling on the B7-H3 expression. So we definitely want to know whether SP1 is involved in this process or not, and how this AR signaling crosstalk with the PTEN/p53 pathway in regulating B three expression in the context of the prostate cancer and the CRPC.
Andrea Miyahira: Thank you. Finally, what are your next steps and what are the steps that you guys are looking at for translating these findings into the clinic?
Di Zhao: Sure. We definitely want to do that for next step. And so, as I mentioned, many approaches has been developed to target B7-H3 and some of them are in clinical trials. So, next step, for a preclinical part, we want to determine whether the combination strategies identified in this study can also apply to other B7-H3 targeted therapies, like a B7-H3 ADC and also a CAR T and bispecific antibodies, something like that. Also, we want to know whether the deficiencies of the PTEN and p53 tumor suppressor genes may synthesize the prostate tumors to this B7-H3-targeted therapy. Also, will collaborate with Dr. Ana Aparicio to run co-clinical trials for some of those regions once we see the promising results from our preclinical model.
Andrea Miyahira: Okay. Well this is so wonderful. Thank you so much for joining me today, Dr. Zhao.
Di Zhao: Thank you so much, Andrea, for inviting me to give you this presentation and the opportunity to introduce our studies. Most importantly, I want to thank Prostate Cancer Foundation to continuously support our research since 2017, and also support myself and my team to do this fantastic research. Yeah, I hope we will have some good translational studies come out in the next few years.