Tailored Therapies Needed to Overcome Immune-Cold Microenvironment of Chromophobe RCC

In an interview with OncLive®, David A. Braun, MD, PhD, provided an in-depth look at an analysis of tumor-intrinsic and microenvironmental mechanisms of impaired antitumor immunity in patients with chromophobe RCC.

Leveraging machine learning and single-cell RNA sequencing (RNA-seq) to analyze tumor samples, Braun and colleagues identified a dearth in 3 fundamental determinants of immune response in chromophobe RCC: decreased T-cell infiltration, a lack of tumor-infiltrating CD8-positive T cells, and decreased tumor specificity.

“This research helps to lay a foundation, and [give us a] roadmap, [of the] problems with immunity within chromophobe, as well as ideas on to how to approach it,” said Braun, an assistant professor of medical oncology, the Louis Goodman and Alfred Gilman Yale Scholar, and member of the Center of Molecular and Cellular Oncology at Yale Cancer Center in New Haven, Connecticut. “Now we have to do the hard work of actually testing [alternate approaches such as T-cell engagers or vaccine-based therapies], and showing that they could work.”

Topics discussed by Braun include the importance of sequencing for improved understanding of tumor biology; potential explanations for observed differences in immune checkpoint expression between chromophobe and clear cell RCC; the applicability of these findings in both preclinical and clinical settings; and the need for further research to develop effective, tailored therapies in chromophobe RCC.

Braun also outlined the rationale for this investigation, study design, and immune defects that were identified for chromophobe RCC in a prior article.

OncLive: What is the relationship between clonal expansion of T cells and tumor specificity? What differences in clonal expansion between tumor subtypes were revealed?

Braun: The clonal expansion of T cells is closely related to the question of specificity. The basic idea is that when a T cell sees its target—in this case, ideally the tumor cell—that T cell divides, resulting in a large clonal population. This is something that can be measured with T-cell receptor sequencing at the single-cell level, allowing us to determine how many T cells share the same T-cell receptor. If there are many T cells that all have the same receptor, it indicates that they must have seen their target and expanded. This suggests that they are likely to be specific for the tumor.

In clear cell RCC, most of the T cells present were clonally expanded, and very few were not expanded. This likely corresponds to the majority of those T cells being specific for the tumor, recognizing their target, and expanding. In chromophobe [RCC], the picture was the exact opposite: very few T cells were expanded. This supports the idea that even the few T cells present are not actually recognizing the tumor as the target and are more likely bystanders incapable of mounting an antitumor effect.

How does this study support the use of RNA-seq as a tool for understanding tumor biology and guiding future therapeutic development?

Sequencing really is what would enable this sort of level of understanding. [It has] changed so much about how we practice oncology, in terms of precision medicine. Its use here is less direct in terms of guiding a particular therapy, but really to develop a fundamental understanding of these tumors. If [these tumors] lack T cells to begin with, the T cells that are there are basically the wrong phenotype, and [they’re not] tumor specific, then our current approach of immune checkpoint inhibition is unlikely to be effective. However, there are lots of other modalities that could bring in and activate T cells effectively. This study hints at he next generation of therapies to explore within chromophobe RCC, but all of that understanding fundamentally lies on the pillar of sequencing. Without single-cell RNA-seq, we never would have been able to develop this level of understanding.

What are the clinical implications of these data?

Up until this point, for patients with many of the non–clear cell histologies, such as chromophobe RCC, there have not been many dedicated clinical trials or clinical investigations based on their biology. [This is] largely due to the practical reality that clear cell RCC is much more common. Typically, a therapy is developed in the clear cell kidney cancer space and then extrapolated to diseases like chromophobe RCC, sometimes with a small trial, sometimes without, and we hope that it will also be effective in chromophobe RCC.

[However], in clear cell RCC, there are many PD-1–expressing, antigen-experienced T cells seen in the tumor, so checkpoint inhibition makes a great deal of sense. In chromophobe RCC, there may be individual tumors where this is true, but in a large number of tumors, it is not. For these cases, other immunotherapy approaches will need to be considered. This does not mean that immunotherapy will be ineffective, but that conventional strategies used for clear cell RCC may not be the right approach. Alternative options might include using T-cell engagers that recruit T cells and activate them in the tumor microenvironment, or vaccine-based approaches to increase antigen-specific or tumor-specific T-cell infiltration into the microenvironment.

How do these findings provide a road map for future research in both clinical and preclinical settings?

This paper will hopefully help to lay that foundation and [serve as a] roadmap that identifies the problems in immunity within chromophobe RCC and gives us ideas on how to approach it.

The next step is to say, “Okay, we have the ideas and hypotheses for how to improve immunity within chromophobe, for instance, recruiting T cells through T-cell engagers or using vaccine-based approaches, but now we need to do the hard work of testing these strategies and demonstrating that they work.” The next levels of investigation will focus on identifying the right targets to effectively augment immunity now that the biology of these tumors is better understood, and then testing these approaches first in a preclinical setting to build confidence, before ultimately moving them into clinical studies. The goal is to do this as rapidly as possible because, every other week, there is a patient in the clinic with chromophobe kidney cancer, and current treatments remain extrapolations from clear cell RCC. There is a need to do better for these patients.

Are there any important study limitations to note?

There are a number of limitations that are worth noting, and I will highlight 2 of them. One is the small study size. There are different ways to perform these sorts of biological studies. One approach is to use very large sets of samples but with relatively lower depth of analysis. There is a huge amount you can learn from numbers, and I think something like The Cancer Genome Atlas is a great example, where there are many more samples with chromophobe RCC that underwent exome sequencing and bulk RNA sequencing, and certainly a huge amount was learned. However, there are limitations in the depth of analysis because of the techniques used.

This paper utilized an alternative approach, which was to use only a few tumor samples but go very deep into the molecular characterization. The limitation [of this approach] is that when you have a small sample size, there are always questions about how much will translate or [can be] validated on a much larger scale. Is this something that is universal in all chromophobe tumors—in 70%, in 50%, in 30%? Those are questions we cannot answer with a small sample size. Taking some of these points and validating them in larger settings will be critical.

The second limitation is something inherent to all of these sorts of genomic studies, which is the issue of heterogeneity. Whenever we do these studies, we get a single, small piece from one part of the tumor, but these are often large tumors. Would a different area of the tumor have slightly different biology? Would a different site, if it is a patient with metastatic disease—not the primary tumor but a metastasis in the lung or the lymph node—have different biology? These are important questions that we still need to answer.

References

1. Labaki C, Saad E, Madsen KN, et al. Tumor-intrinsic and microenvironmental determinants of impaired antitumor activity in chromophobe renal cell carcinoma. J Clin Oncol. 2025;43(23):2639-2654. doi:10.1200/JCO-25-00234
2. Hazell, N. Novel insights into chromophobe renal cell carcinoma biology and potential therapeutic strategies. News Release. Yale School of Medicine. July 2, 2025. Accessed August 13, 2025. https://medicine.yale.edu/news-article/novel-insights-into-chromophobe-renal-cell-carcinoma-biology-and-potential-therapeutic-strategies/