Immunotherapies have been successful in treating many cancer conditions. However, not much success has yet been achieved in metastatic castrate-resistant prostate cancer (mCRPC). A study published March 2 in Clinical Cancer Research has revealed new insights into why immunotherapies don’t tend to work as well in prostate cancer.
The team, led by Akash Patnaik, MD, PhD, MMSc, Assistant Professor of Medicine at the University of Chicago Medicine Comprehensive Cancer Center, discovered that the immune system promotes the growth of cancer — instead of suppressing it — through recruitment of abnormal tumor-associated macrophages (TAMs) that express PD-1 into the tumor microenvironment.
Therapy resistance spells trouble for treatment
Hormonal therapies such as androgen deprivation therapy (ADT) and chemotherapies are first-line treatment options for treating metastatic prostate cancer. Although these therapies can improve the odds of survival, most patients will find their cancer returning. Chemohormonal therapies can also contribute to the development of aggressive forms of treatment-resistant prostate cancer.
One such aggressive form of advanced prostate cancer results from the loss of a particular gene called phosphatase and tensin homolog (PTEN), which drives hyperactivation of the phosphatidylinositol kinase-3 (PI3K) growth and survival pathway. As a result, cancer cells grow out of control.
“Given that PTEN/PI3K pathway alterations are one of the most frequent ‘drivers’ of human disease across all cancers, there have been several pharmaceutical efforts to target this pathway over the past decade. However, single-agent responses have been very limited to date,” said Patnaik.
Recent clinical studies have found that PI3K inhibitors in combination with ADT in mCRPC patients have only limited efficacy. To understand the mechanisms underlying the response and resistance to combinatorial ADT/PI3K inhibitors, Patnaik and his team performed simultaneous preclinical studies at in a PTEN-deficient mouse model which also lacked p53, another common alteration in human cancer that drives aggressive disease.
They discovered that PD-1-expressing immunosuppressive TAMs were recruited following ADT/PI3K inhibitor treatment and blocked anticancer immunity mediated by macrophages. To test whether blocking PD-1 would increase the antitumor efficacy, PD-1 checkpoint immunotherapy was added to the ADT/PI3K inhibitor combination. The results showed a significantly increased overall response rate in mice.
Originally published in The Forefront, 3/11/2023