PROJECT SUMMARY Emerging data highlight previously unappreciated connections between cancer and scleroderma (SSc). Using autoantibodies as probes to identify clinically and biologically relevant SSc subgroups, we have shown that patients with anti-RNA polymerase III (POLR3), anti-RNPC3 or (monospecific) anti-Ro52 antibodies are more likely to have a cancer emerge close to the time of scleroderma onset.1-6 In contrast, antibodies against centromere, U1RNP, or Th/To proteins appear to define a subset of SSc patients with a lower cancer risk.3, 6, 7 Interestingly, patients with anti-POLR3 or anti-Ro52 who are positive for additional autoantibodies, including anti- RPA194, anti-Th/To and anti-U1RNP, do not have increased cancer risk suggesting that increased breadth of the immune response may be cancer protective.6-8 These data strongly suggest that SSc-specific autoantibodies may be powerful tools for cancer risk stratification. It remains unknown whether (i) cancer is a driver for the development of autoimmunity more broadly in SSc, (ii) diversified immune responses are exerting potent anti-tumor pressure, (iii) autoantibody strength and breadth are predictive of incident cancer diagnosis, and (iv) cancer emergence and elimination influences changes in SSc clinical outcomes and immune responses. The proposed studies will use prospective and retrospectively collected data and biospecimens from two well-characterized SSc cohorts to study the key relationships between malignancy, the immune response and clinical expression of SSc. We will accomplish this through the following specific aims: Aim 1 will test whether novel tumor markers, genetics, SSc autoantibody and clinical features associate with incident cancer diagnoses in two large SSc cohorts. These data will provide a critical foundation for the development of clinically actionable, targeted and evidence-based approaches for cancer detection in patients with new onset SSc. Aim 2 will define whether cancer emergence or elimination influences scleroderma clinical outcomes. We will address whether cancer remission associates with clinical improvement in SSc and qualitative or quantitative changes in the autoantibody responses across this transition. In a prospective study, we will test whether subclinical malignancy assessed by liquid biopsy shapes the immune response and SSc disease process. Among those with a new clinical cancer diagnosis, we will assess whether the mutational signature in the cancer matches that observed in circulating tumor DNA. These data, rigorously generated in two of the largest SSc cohorts in the US, are likely to provide important insights with direct relevance to management and therapy of SSc, while also illuminating the mechanisms operating at the interface between cancer, anti-tumor immunity and autoimmunity in SSc. This approach is also relevant to other autoimmune rheumatic diseases in which cancer and rheumatic disease onset are temporally linked.