PD-1 Expression on Monocytes Potential Immunotherapy Biomarker in RCC

Mohammed Haseebuddin, MD

An elevated preoperative classical monocyte (CM) PD-1 mean fluorescence intensity (MFI) level and lower CM (%) was linked to poor survival in patients with clear cell renal cell carcinoma (RCC) and might identify a population that would benefit from immunotherapy.

In an analysis presented by Mohammed Haseebuddin, MD, at the 2016 AUA Annual Meeting, blood samples were obtained from 90 patients with RCC prior to partial or radical nephrectomy and 25 age-similar healthy donors. Elevated CM PD-1 was defined at the third quartile level of CM PD-1 expression (784 MFI) in healthy donors.

At a median follow-up of 41 months, 10 patients with clear cell RCC had died, none of whom were diagnosed with low-grade disease. Results showed that the mean proportion of CM (%) was lower in those who died of disease versus censored (64% vs 52%; (P = .029).

Data showed that patients with CM PD-1 expression >784 MFI had lower cancer-specific survival (CSS) versus patients with CM PD-1 <784 MFI (P = .017). CSS at 24 months for CM PD-1 MFI >784 was 79.3% (95% CI, 59.5-90.1) versus 97.0% (95% CI, 80.4-99.6) for CM PD-1 MFI <784.

OncLive: What was the objective of this study?

In an interview with OncLive, Haseebuddin, a fellow in Urologic Oncology at Fox Chase Cancer Center, discusses the overall significance of this study and the challenges with using PD-1 as a biomarker in patients with clear cell RCC.Haseebuddin: First, we need to define what classical monocytes are. When you have a tumor growing in the kidney, for example, the immune cells are also infiltrated and, sometimes, the types of immune cells do matter. There are several studies that have identified that tumor-associated macrophages are important. They come in 2 different types.

For cancers to grow, they need to use the angiogenesis mechanism of these macrophages. Monocytes are actually progenerated cells to macrophages. There are 3 different types of monocytes: classical, intermediate, and non-classical. It is thought that the classical monocytes are more like proinflammatory monocytes, which then enter the tissue and act against cancer. It is not yet clear what the exact roles are of the other 2 monocytes. However, what is true is that all of these monocytes do play a role.

What are the potential implications of this research?

There is a lot of information about PD-1, or checkpoint, inhibitors that allow the immune system to go up and down in its responses against cancer. If you inhibit this, you increase the activity of these immune cells against cancer. We thought that PD-1 expression in select patient populations affects survival. Also, we thought that the monocytes seem to play a central role in the immune system; therefore, perhaps PD-1 expression on monocytes may be important for survival.We looked at about 68 patients with clear cell RCC and did flow cytometry on them, and coordinated that with survival and compared them also with healthy non-cancer patients. Our findings were, essentially, that PD-1 expression on classical monocytes does demonstrate a poor prognosis—independent of grade, stage and other clinical variables.

What might be the next steps?

There is controversy surrounding the efficacy of PD-1/PD-L1 testing. How do these results play into that?

Are there challenges with some patients who may benefit from not testing as PD-1—positive?

The question is, “What patients do benefit from immunotherapy?” We have also shown, in the past, that PD-1 expression does decrease after surgery. This correlation that we have with survival is the preoperative PD-1 expression. If we can tell what patients may be poor prognostic indicators, even before surgery, we can perhaps identify those who are better treated with immunotherapy. That is our goal.We should incorporate this data with clinical trials that are studying neoadjuvant immunotherapy and see whether patients, with high levels of PD-1 on monocytes, for example, respond better to immunotherapy or not.That’s an excellent question. There are different types of blood or tissues samples that do staining. The tissue-based staining on PD-1/PD-L1 is not quite there yet. There are several antibodies that are there. What we are talking about in this study is actually serum-based markers. This is noninvasive and you are able to identify PD-1 expression.In clinical trials, we found that PD-L1 expression on the tumor is not a predictor of response to therapy. When you give a PD-1 inhibitor to those patients who have PD-L1—negative staining in the tissue, they do still benefit. It’s not a perfect marker.

Why does this disconnect exist?

We’re trying to compare PD-1 expression in the peripheral blood lymphocytes to the expression in the tissue and see if one versus the other may be associated with better response. For therapy to work, it has to play both parts. It is not just the tissue that would express PD-1; it is also the peripheral blood. If you have a patient with no PD-1 expression on the blood lymphocytes but has a high expression in the cancer, it may not necessarily work.PD-1 expression on the peripheral blood lymphocytes is an independent phenomenon than cancer itself. Cancers try to modulate the immune system, so you need an understanding of both—not just the cancer. You also need to have an understanding of what the peripheral blood lymphocytes are doing, as well. If this were to continue forward and checkpoint inhibitors were to be used in this patient population, what impact would that have?

There is a significant need for checkpoint inhibitors right now in terms of adjuvant trials in localized kidney cancer. None of the targeted agents have really shown any decreases in recurrence-free survival.

Previous data showed that PD-1 levels are highest before surgery and then decrease after surgery. If that really is true, we can identify those who may benefit from this therapy who have high levels of PD-1 and treat them with this in a neoadjuvant fashion, even before the tumor is taken out.

Our hope is that it would decrease recurrences and improve recurrence-free survival. There are currently a couple of clinical trials out of Johns Hopkins Medicine and Dana-Farber Cancer Center that are currently trying this.

Haseebuddin M, MacFarlane A IV, Ruth K, et al. PD-1 expression on classical monocytes (CM) is an independent predictor of cancer specific survival in clear cell renal carcinoma (ccRCC). Presented at: 2016 American Urological Association Annual Meeting; May 6-10, 2016; San Diego, CA. Abstract: MP92-01.

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