GoKawiilIn this study we provide evidence for the clinical relevance of thymic health in immuno-oncology. We found that high thymic health was consistently associated with improved outcomes across a real-world cohort of 3,476 patients with various cancer types who were treated with ICIs. In our analysis, thymic health was a particularly strong indicator of outcome in lung cancer and melanoma—cancer types that are commonly treated with immunotherapy. Associations of thymic health and outcomes were also found in patients with breast and renal cancer, indicating that the prognostic relevance of thymic health is tumour-agnostic. Analyses in the independent and prospectively collected TRACERx cohort provide evidence that radiographic quantification of thymic health is a proxy of thymic functionality and related to immune competence. These findings suggest that an individual’s immune health relates to immunotherapy outcomes, highlighting the potential importance of considering host-specific factors as biomarkers, rather than relying solely on the tumour-centric biomarkers that at present dominate the field.
Although immunotherapy is increasingly being applied in oncology, only a subset of patients respond9,10,11. To optimize treatments and expand the population of patients who benefit from immunotherapy, improved biomarkers are needed to better estimate individual prognosis in this context. Despite the fact that ICIs derive their anti-tumour properties from T cells and their capability to invade and potentially destroy neoplasms, precision medicine in immuno-oncology has so far focused on biomarkers that predominantly capture cancer-specific biology12,13,14. We define thymic health as a universal prognostic biomarker on the basis of the radiographic characteristics of the thymus itself—an immune organ that is crucial for T cell maturation and generating a diverse T cell repertoire. These characteristics are essential for detecting foreign antigens and required for immunotherapy response.
Our results show that thymic health enables robust immuno-oncology prognostication using routine, standard-of-care thoracic CT scans without additional imaging, patient burden or delay. Although further studies are required to define biomarker-specific thresholds and assess negative and positive predictive values, our results nevertheless provide evidence that thymic health could serve as an instantly available, integral biomarker for immuno-oncology, either as a stand-alone measure or in combination with measures of PD-L1 and TMB. PD-L1 remains a well-established predictor of response, and, as expected, patients with low PD-L1 expression had worse survival following immunotherapy in NSCLC. However, our results suggest that thymic health adds independent prognostic value beyond PD-L1 by capturing the host’s immune competence. Together, these markers reflect distinct biological axes, tumour immune evasion and immune competence, and their combined assessment might offer a more complete framework for precision immuno-oncology. Our findings thus suggest that host-based biomarkers that quantify the state of adaptive immunity should be incorporated into the precision-medicine-based stratification of patients.
We show that we can identify patients with different cancer types who are likely to benefit from immunotherapy. It is conceivable that our approach could further accelerate the adoption of immunotherapy in new indications in which only a small subset of patients might benefit, and for which no biomarkers currently exist. Although higher thymic health was consistently associated with improved outcomes, the threshold for benefit seemed to vary across cancer types. In some cancers, both high and average levels of thymic health were associated with better outcomes; in others, only high levels were. This suggests that thymic health acts along a gradient, with tumour-type-specific factors, immune responsiveness and specific treatment protocols also being important factors18,29. A similar pattern has been reported for TMB, which showed stronger predictive value in some cancers, such as melanoma or NSCLC, than in others, such as breast or oesophageal cancer29. Similarly, our results suggest that thymic health assessment could facilitate the identification of patients at risk of poor outcomes following immunotherapy. Indeed, preventing non-beneficial immunotherapy is essential. It increases quality of life by reducing the risk of unnecessary adverse events, and facilitates and speeds up the selection of more favourable alternative treatments. Furthermore, it reduces population healthcare costs by avoiding unbeneficial, toxic21 and expensive therapy among these individuals.
The biological mechanism behind the observed poorer clinical outcomes seen in individuals with low thymic health is most likely to be a reduction in the output of naive T cells. This is supported by our findings in the TRACERx cohort, in which we found that relative to patients with low thymic health, those with high thymic health had significantly higher levels of sjTRECs, a by-product of thymic T cell production that is considered to be a direct readout of thymic activity23. Moreover, we showed a correlation between higher thymic health and increased T cell diversity. A similar link between the state of the thymus and T cell diversity has been reported previously20,24. Our findings thus suggest that the state of the adaptive immune system is crucial for outcomes and that adaptive immune capacity is reflected in thymic characteristics.
Notably, thymic health was prognostic in patients with advanced NSCLC receiving immunotherapy, including those who had previously been treated with cytotoxic chemotherapy. Effect sizes were strongest in the first-line immunotherapy setting, with a consistent—although non-significant—trend towards thymic health and pretreatment interaction, suggesting that the association of thymic health with outcomes is particularly relevant before chemotherapy-induced immune suppression. Given previous evidence that chemotherapy can impair thymic function19,30, our results raise the possibility that maintaining thymic health could influence the long-term benefit derived from systemic cancer therapies. Of note, the persistence of prognostic value in pretreated patients receiving immunotherapy underscores the robustness of thymic health as a host immune-competence marker even in this subset of patients. Our results might have broader implications for personalized cancer treatment31. It has previously been shown that the balance between myeloid and lymphoid cells changes with age, favouring an innate immune response. Work in mice has shown that specific depletion of myeloid precursor stem cells can restore the balance between lymphoid and myeloid compartments and reinvigorate the immune system32. Similar results could potentially be obtained in humans using similar approaches, or through specific treatments aimed at restoring thymic function33. However, any such approach to manipulate the basic elements of the immune system will require rigorous preclinical trials.
Previous studies found that thymic involution—that is, a reduction in thymic health—was a driver of immunosenescence and increased disease risk in adults34,35,36. Attempts have been made to visually score thymic involution on CT scans by estimating the degree of fatty degeneration in the thymic bed, and although no outcome implications were reported, these studies found basic associative results that are consistent with our study, such as differences in thymic involution depending on sex, age and smoking status24,37,38. Conversely to our results, these studies estimated that most adults have a fully fatty degenerated thymus24,37, whereas we found significantly improved health outcomes in association with high and average thymic health, representing 75% of the examined pan-cancer population. This indicates that using an automated deep-learning approach allows for a more detailed thymic health assessment. Indeed, our findings of maintained thymic function in most adults are supported by our findings of positive associations with T cell output in the independent TRACERx cohort; by previously reported sustained T cell output in presumed fully fatty degenerated thymic glands24; and by mathematical modelling35. Consistent with our findings and our accompanying article39, lifestyle might be directly associated with thymic health, emphasizing the need for studies that address potential preventive or regenerative strategies34,40,41.
In our study, we investigated various cancer types across independent cohorts, comprising the real-world Harvard-NSCLC and Harvard-PAN cohorts for outcome analyis and the prospective observational TRACERx study for biological correlations. We provide robust evidence of a positive association between thymic health and outcomes in patients with various cancer types who were treated with immunotherapy, strongly suggesting that thymic health should be assessed for the stratification of patients for immunotherapy treatment. This has crucial implications beyond cancer and for current clinical practice; for example, in cardiothoracic surgery and radiation oncology, the thymus is currently not considered an essential organ, and could potentially be removed20 or included in high-dose irradiation fields. However, in both instances, the thymus might be preserved with minimal adjustments to current clinical practice. Our results, supported by those of others20, suggest that there may be benefits to preserving the thymus. However, further studies are required to define the specific clinical context in which this applies. We emphasize the importance of the thymus for adult health in our accompanying article39, in which we demonstrate the relevance of the thymus for long-term health and lifespan in more than 25,000 presumably healthy individuals.
One limitation of our study is that although the included patients encompass a wide age range for both sexes, they are predominantly white, and further testing in diverse ethnic populations is required. Before the thymic-health model can be applied in clinical settings, it is essential to prove generalizability across scanners, institutions, countries and populations. Given these limitations, the presented thymic-health analyses were done using population-specific thresholding, and no universal cut-offs can be assumed at this time. However, because the development and application of the thymic-health model were performed in fully independent datasets, with high robustness as demonstrated by test–retest stability, successful external validation is likely. The next steps will include international and external validation in diverse populations of people with cancer.
Although our study design, which did not include a matched non-immunotherapy comparator, prevents the direct assessment of the predictive implications of thymic health, our analysis is consistent across multiple cohorts and cancer types. However, further work in properly powered cohorts will be required to determine whether a patient’s thymic health could serve as an independent biomarker of immunotherapy response that is equal to established tumour-intrinsic biomarkers such as PD-L1 or TMB, and that extends to cancer types other than NSCLC. This argues strongly that thymic health is a functionally important and independent component of tumour-agnostic immunotherapy efficacy.
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