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The Negative Impact of Obesity on the Tumor Microenvironment in Colon Cancer: Results From a Prospective Trial
Devin C. Flaherty*1, Simon Lavotshkin5, John R. Jalas3, Hitoe Torisu-Itakura6, Myung S. Sim2, Delphine J. Lee4, Anton J. Bilchik1
1Surgical Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA; 2Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA; 3Pathology, Providence Saint John's Health Center, Santa Monica, CA; 4Translational Immunology, Dirks/Dougherty Laboratory for Cancer Research, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA; 5Grossmont Surgical Associates, La Mesa, CA; 6Medicines Development Unit, Eli Lilly Japan K.K., Akasaka, Minato-ku, Tokyo, Japan
Background: Elevated body mass index (BMI) is a risk factor for developing colon cancer. The association of tumor mismatch repair (MMR) status in colon cancer and obesity is not well understood. We hypothesize that MMR deficiency in colon cancer is associated with a lower BMI and improved patient outcomes due to a more robust tumor immune microenvironment.
Methods: Patients were randomly selected from a prospectively collected cohort enrolled in an ongoing, international, phase II trial of surgical treatment and nodal ultrastaging for AJCC stage I-III colon cancer. Tumor MMR status, a surrogate marker for microsatellite instability, was determined by immunohistochemistry (IHC) for MLH-1, MSH-2, PMS-2, and MSH-6. Tumor expression of five immunomarkers (CD3+, CD4+, CD8+, CD68+, and FOXP3+) was assessed by IHC and digital image analysis. Tumor MMR status and T cell densities were correlated with TNM staging, demographic and clinicopathologic variables, and 5-year disease-free survival.
Results: Within our cohort, 73 patients fit predetermined inclusion criteria. 62 patients were MMR-proficient (85%), and 11 MMR-deficient (15% - all right-sided). Females (n=33) had a higher incidence of MMR-deficient tumors (24%) compared to males (7.5%, p=0.047). Patients with MMR-deficient tumors had a significantly lower BMI than those with MMR-proficient tumors (p=0.006) (Table). Interestingly, patients with MMR-deficient tumors demonstrated no recurrence during a median follow-up of 29 months. Correlating tumor immunoprofile with MMR status and patient BMI, the presence of the T cell CD3+ was inversely associated with proficient MMR status (CD4+/CD3+ at the tumor center, p=0.040). Further, the presence of the cytotoxic T cell CD8+ at the tumoral invasive margin and tumor center was significantly associated with a BMI less than 30 (Figure, p=0.003). Also, a higher density of the regulatory T cell FOXP3+ was found at the tumoral invasive margin in non-obese patients (p=0.005). Multivariable Cox proportional hazard analysis considering clinical variables, MMR status, and immunomarkers found CD3+ counts (HR=0.319 [0.166-0.612]), CD8+ counts (HR=0.611 [0.444-0.840]), and number of tumor-positive lymph nodes (HR=1.192 [1.037-1.369]) to be prognostic of disease-free survival.
Conclusions: This is the first study to demonstrate a correlation between MMR status and BMI by using prospectively acquired data from a clinical trial in which surgical and pathological management of colon cancer adhered to strict quality measures. Further, colon cancer in patients with a lower BMI in our cohort harbored increased densities of regulatory and cytotoxic T cells, thus indicating increased intratumor immunity, and suggesting an unexplored link between MMR status and the tumor immunoprofile in colon cancer.
Demographic and Clinicopathologic Characteristics
| Characteristic | MMR-Proficient | MMR-Deficient | p-value | Gender, n (%)
Male
Female | 37 (60)
25 (40) | 3 (27)
8 (73) | 0.047 | | BMI (mean) | 26.25 | 22.16 | 0.006 | Tumor location, n (%)
Left
Right | 36 (58)
26 (42) | 0 (0)
11 (100) | <0.001 | Tumor depth, n (%)
T1/T2
T3/T4 | 10 (16)
52 (84) | 1 (9)
10 (91) | 0.548 | N stage, n (%)
N0
N1
N2 | 28 (45)
27 (44)
7 (11) | 6 (55)
4 (36)
1 (9) | 0.847 | AJCC stage, n (%)
I
II
III | 7 (11)
21 (34)
34 (55) | 1 (9)
5 (45)
5 (45) | 0.761 |
MMR = mismatch repair; BMI = body mass index; AJCC = American Joint Committee on Cancer  Logarithmic distribution of the cytotoxic T cell CD8+ in cbese vs. non-obese patients. IM = invasive margin; CT = tumor center.
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