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Do tumor-infiltrating lymphocytes predict melanoma outcomes?

Kathryn Schwarzenberger, MD

Clinical Applications

Dr. Schwarzenberger is the physician editor of DermWorld. She interviews the author of a recent study each month. 

By Kathryn Schwarzenberger, MD, FAAD, November 1, 2022

In this month’s Clinical Applications column, Physician Editor Kathryn Schwarzenberger, MD, FAAD, talks with John T. Vetto, MD, FACS, FASA, from Oregon Health and Science University, about his Cancer paper, ‘Is the presence of tumor-infiltrating lymphocytes predictive of outcomes in patients with melanoma?’

DermWorld: We very much appreciate your advancing the field to help us all improve our management of patients with melanoma. Since not all dermatologists read Cancer, would you summarize your recently published study looking at tumor-infiltrating lymphocytes (TIL) in melanoma? What exactly are TILs?

Headshot for Dr. Vetto
Dr. Vetto: Tumor infiltrating lymphocytes (TIL) are immune mononuclear cells consisting of multiple immune cell types (CD4, CD8, antigen presenting cells [APCs], etc.) found within tumors. Their presence has long been felt to represent an immune response to the tumor. Because melanoma is thought to be an immunogenic tumor (i.e., can elicit a host immune response), the presence of TIL has been of particular interest since 1989 when Dr. Wallace Clark and colleagues described a system to quantify them (absent, non-brisk, and brisk).

DermWorld: What did you look for in your study, and what did you find?

Dr. Vetto: Our study sought to determine if the presence of TIL in melanoma could be correlated with sentinel lymph node (SLN) status and with tumor outcomes. Using a large, prospective, international, collaborative database (the Sentinel Lymph Node Working Group [SLNWG] database), we found that the presence of TIL predicted for a negative SLN (no tumor in the SLN when it was removed and studied pathologically). The level of TIL (using Clark’s system) was directly correlated with melanoma-specific survival (MSS) when the effect of the SLN was excluded from the analysis and was also correlated with regression in the primary tumor. The absence of TIL and a positive SLN resulted in worse MSS, whereas the absence of TIL and a negative SLN did not. Taken together, these results suggest that the presence or absence of TIL may correlate with tumor regression, SLN status, and patient outcomes.

DermWorld: Were you expecting these results? Were there any surprises?

Dr. Vetto: Our results confirm those of smaller studies suggesting that TIL may be prognostic in melanoma although ours are the first to clearly delineate the relationship between TIL and the SLN. Our findings emphasized that the presence of TIL predicts for a negative SLN, whereas the combination of the absence of TIL and a positive SLN is predictive of measurably worse outcomes.

DermWorld: How do you think clinicians should use this information? Can we rely on the presence of TILs to help us determine the need for sentinel lymph node biopsies?

Dr. Vetto: While there are many tools to predict the likelihood that a given patient’s SLN may be positive (nomograms, genetic expression profiling, etc.) our data suggest that the presence of TIL predicts for a negative SLN, so that the presence of TIL in a patient in whom NOT doing a SLN biopsy is being considered may add support for that decision, as does our finding that the level of TIL correlated with better MSS when the effect of the SLN was excluded (i.e., prior to the SLN biopsy in the pre-operative setting). Alternatively, the absence of TIL and positive SLN marked patients with worse outcomes, so that the absence of TIL may spur the performance of a SLN biopsy to determine if the patient is at particularly high risk.

Our findings can therefore assist in the pre-operative conversation for patients being considered for SLNB. The presence of tumor in the SLN, however, is dependent on many factors and therefore the level of TIL in the primary tumor cannot be used as a stand-alone determinant of whether a SLN biopsy should be done. Also, our findings are based on retrospective analysis and need validation by a prospective study to add reliability.

DermWorld: And then, of course, there is gene expression profile testing for melanoma. In an ideal world, how do you imagine us using all these different tests, and in which patients?

Dr. Vetto: At present, a score called the iGEP score has been developed combining the recurrence score (from 0-1) of the 31-GEP with tumor factors (Breslow Thickness, ulceration status, mitotic rate) and patient age to produce a to-the-decimal-point estimate of the chance for SLN positivity. The results of our study suggest that the iGEP might be further improved by adding the level of TIL. This could be the subject of future study. For the present, discussions regarding whether to do the SLN biopsy (in any patient in whom it is being considered) that currently are being assisted by consideration of the GEP and iGEP could also take into account the level of TIL.

DermWorld: Can you think of any additional information we can get from TILs?

Dr. Vetto: The presence of TIL in melanoma is not only prognostic, as our study demonstrates, but TIL can also be exploited for treatment. Immune therapies, both systemic (such as checkpoint inhibitors) and intralesional (such as talimogene laherparepvec) work by activating CD8 T cells (cytotoxic, so-called “killer” T cells) that recognize tumor antigen, including those in TIL.

A well-established form of adoptive immunotherapy for advanced melanoma involves removing TIL from tumor samples, growing them in interleukin-2 (IL-2) to stimulate the growth of tumor-reactive CD8 T cells, and infusing those cells (along with I.V. high dose IL-2) back into patients who have been pre-treated with lymphodepleting chemotherapy to remove immunosuppressive cells. This treatment is obviously toxic, time consuming, and fraught with barriers, including lack of TIL, failure of TIL to grow in culture, and serious adverse events, mainly from the lymphodepletion and high-dose IL-2 therapy. Therefore, the best candidates for this “TIL therapy” have a good performance status, a life expectancy of at least three months, and good hepatic, renal, and hematopoietic function. Multiple studies have reported objective and complete response rates for TIL therapy in melanoma of up to 55% and 23%, respectively.

John T. Vetto, MD, FACS, FASA, is professor of surgery in the division of surgical oncology and professor of dermatology at OHSU School of Medicine. He is a speaker for Castle Biosciences. His paper appeared in Cancer.

Disclaimer: The views and opinions expressed in this article do not necessarily reflect those of DermWorld.

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