Figure S1. 1g tumors (weeks) ikras. Lean Obese. Lean Obese 25 KPC

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1 Fgure S 5 Tme to develop g tumors (weeks) 5 5 Tme to develop g tumors (weeks) 5 5 KRS KPC Fgure S. Effect of obesty on tumor ntaton. Tme to develop tumors of about g n KPC and KRS mce fed low or hgh-fat det. Data are shown as mean ± SEM. P values were determned by the Student t-test., p<.5.

2 Fgure S C57l/6 / PN FV / Vsceral WT Vsceral WT /fat nterface C Vsceral WT Spleen Vsceral WT Masson s Trchome KRS Vsceral WT Fgure S. dpose tssue tumor nteracton. () Representatve pctures of PN, and KRS tumors nvadng vsceral whte adpose tssue (WT) n obese mce. () Representatve ultrasound mage of a PN tumor 9 days after orthotopc mplantaton n an obese mouse. s seen nvadng the local vsceral WT. (C) ddtonal fgures depctng an assocaton of fbross wth adpocytes n tumors from obese mce. Masson s trchrome stanng n tumors revealed a predomnance of fbross content n areas rch n adpocytes or adjacent to vsceral adpose tssue. Scale bars: 5 μm (upper panels, lower left panel), 5 μm (lower rght panel).

3 Fgure S3 F G % MT Stanng / ROI Collagen-I / tumor (%) PN 6 sze (mm) Hyaluronan PN α C % hyaluronan / tumor 3 H D Hyaluronan PN E asm expresson (normalzed to -actn) 5 3 PN T KO Fgure S3. Correlaton of collagen-i levels wth tumor sze, co-expresson of collagen-i and hyaluronan n PSCs, and mpact of obesty on desmoplasa and tumor hyaluronan levels. () Quantfcaton of fbross/desmoplasa wth Masson s trchrome (MT) stanng n tumors from lean and obese mce (n=3-8 ROI, 3- tumors/group). Representatve pctures n fgures and SC. () Correlaton between expresson of collagen-i levels and tumor area (k. tumors) n both lean and Collagen-I αsm DPI obese settngs. No statstcal dfference was acheved (Pearson s test) n ether metabolc settng. (C) Representatve pctures () and quantfcaton () of hyaluronan (H) bndng proten (HP, whch detects H) stanng n tumors from lean and obese mce. Scale bars: mm (n=3-6/group). (D) Quantfcaton of H measured by ELIS n PN tumors from lean and obese mce (n=3-6/group). (E) Effect of obesty and of IL-ß nhbton or T blockade on the expresson of αsm and vmentn n PN tumors. (E-) Each lane corresponds to one ndvdual tumor. (E-) Quantfcaton of proten expresson normalzed to ß-actn. The obesty-augmented expresson of αsm and vmentn was normalzed after IL-ß or T blockade. (F) Immunofluorescence demonstratng that αsm-expressng PSCs assocate wth collagen- expresson n PN tumors. Whole tumor stanng depcted n the left pcture; capton of an area where the two markers overlap n the center pcture; amplfcaton of the center fgure on the rght. Scale bars: mm (fleft panel), μm (center panel), 5 μm (capton). (G) Representatve pcture of co-expresson of αsm wth collagen-i and hyaluronan n tumors. Scale bar: μm. P values were determned by the Student t-test n and C-D, and one-way NOV n E. Data n -E are shown as mean ± SEM., P <.5;, P <.. IL- nh. T-KO IL-ß nh. T-KO IL-β nh Vmentn expresson (normalzed to -actn) 3 IL-ß nh. αsm Vmentn β-actn IL- nh. T-KO T-KO

4 Fgure S PN whole tumor extracts C-IX Hf-α β-actn Fgure S. ddtonal Western blottng data from PN tumors. Effect of det-nduced obesty on tumor hypoxa. Each lane represents the proten expresson of hypoxa markers n ndvdual PN tumors. Denstometrc analyss (fold-change compared to the lean group) normalzed to ß-actn s ncluded n data presented n Fg3.

5 Fgure S5 MERGE DPI T αsm D F % dose njected/ g tssue PN volume (mm 3 ) PN Losartan Losartan Los Treatment ntaton % dose njected/ g tssue 3 Los Day Day 5 Day 9 Day Days after tumor mplantaton Losartan Losartan G Fold Regulaton Mean arteral blood pressure (mmhg) E % of vessel area / tumor 8 6 Los lean Losartan Losartan α-sm ngotensnogen Colα Col3α Colα3 Decorn Mmpa Mmp Mmp3 Mmp9 Mmp9 Tmp3 Tmp Lysl oxdase PN ody weght (grams) 6 Day Day % αsm / 3 Losartan TKO PN Los Los Losartan TKO Day Day Day Day Day Day Day Day Day Day Fgure S5. ddtonal effects of T- nhbton on obesty-aggravated desmoplasa, perfuson and drug delvery. () Double mmunofluorescence for αsm and T receptor n two orthotopc PDCs. ~7% of actvated PSCs expressed T receptor n PN and ~35% n. Scale bar: 3 μm (left panels), 5 μm (rght panel). () Effect of losartan on the expresson of fbross/desmoplasa-related markers n tumors. mrn expresson of markers of tumor fbross/desmoplasa was ncreased n tumors n obese mce,and was reverted by losartan. Losartan dd not alter these markers n lean mce (3- samples/group were pooled for the PCR array analyss). mrn expresson n control groups s also depcted n Fg.. (C) Effect of losartan treatment on αsm expresson n PN tumors. Losartan-nduced a tendency for reduced tumor αsm proten expresson n obese but not lean settng (n=3-6/group). (D) Effect of obesty and losartan treatment on PN tumor growth. Volume at day 5 and 9 was measured by ultrasound. Losartan prevented the accelerated tumor growth n obese settng (n=3-6/group). (E and F) Effects of losartan on tumor perfuson (E) and chemotherapy delvery (F) n PN and tumors n obese and lean mce (n=-8/group). (G) Effect of losartan treatment on mean arteral blood pressure n PN tumor-bearng mce (n=3-5/group). lood pressure decreased ~7% after 7 days of treatment wth losartan (9mg/kg). (H) Effect of T blockade on body weght on mce day days after PN tumor mplantaton. P values were determned by two-way NOV n C-H. Data n C-H are shown as mean ± SEM., P <.5;, P <.,, P <.,, P <.. Vessels (CD3+) Los Perfused vessels (CD3+/lectn+) H C Los Los % of vessel area / tumor 3 Vessels (CD3+).7 Perfused vessels (CD3+/lectn+)

6 Fgure S6 Immune cell / % of CD5+ cells 3 PN Fgure S6. ddtonal data on the effect of obesty on mmune cell nfltraton n tumors. () Obesty promoted nfltraton of myelod Gr-(+)F/8(-) cell populaton n tumors n obese mce. Quantfcaton normalzed by total CD5 leucocytes (n= tumors/group). () Representatve flow cytometry scatter plots of CD5(+)CDb(+)Ly6G(+) tumor-assocated neutrophls (TNs) n PN tumors n lean and obese settng Data n are shown as mean ± SEM. P values were determned by the Student t-test., P <.5. Fgure S7 TN-D Ly6G Ly6G CDb+ Gr+/F8- TN TN CDb TN CDb PN tumors TN % of vessel area/tumor 5 5 % of CD3 that colocalze wth lectn (n total CD3+ stan) CD PN Lectn+ TN-D Double + TN-D Fgure S7. Effects of TN depleton on vessel perfuson n obese mce. () Representatve FCS scatter plots of CD5(+)CDb(+)Ly6G(+) tumor-assocated neutrophls (TNs) n control and TN-depleted obese mce. Ly6G specfc nhbton led to a sgnfcant reducton (~9%) of the Ly6G(+) cell populaton n PN tumors from obese mce. () Effect of TN depleton on vessel perfuson n tumors n obese anmals. (-) % of CD3(+), lectn(+) or double postve vessel densty n the vable area of whole tumors. (-) % of CD3 expresson that co-stans wth lectn n PN and tumors (n=-6 tumors/group). Data n are shown as mean ± SEM. P values were determned by the Student t-test.

7 Fgure S8 Proten concentraton IFN- IL- IL- IL- IL-6 CXCL- TNF- mrn levels (Fold change) 3 IL- IL-5 IL- CCL CCR Fgure S8. Effect of obesty on cytokne profle n tumors. () Obesty assocated wth ncreased levels of IL-ß n tumors n obese mce (n= tumors/group). () mrn expresson of markers of mmune suppresson n tumors from lean and obese mce, revealng an ncrease wth obesty. Data normalzed to lean group. 3- samples per group were pooled for the PCR array analyss. Data n are shown as mean ± SEM. P values were determned by the Student t-test., P <.5. Proten concentraton Fgure S9 PN TN-D CXCL- TNF- IL- Fgure S9. Effects of TN depleton on tumor cytokne expresson n obese mce. TN depleton reduced the expresson of CXCL- (IL-8, KC), and tended to reduce the expresson of TNFα and IL- n PN tumors from obese mce. Data are shown as mean ± SEM. P values were determned by the Student t-test., P <.5.

8 Fgure S Log Proten concentraton. IFN-γ IL- IL- IL-β PN IL- IL- IL-5 IL-6 CXCL-.59 Fgure S TNF-α IFN-γ IL- IL- IL-β Losartan IL- IL- IL-5 IL-6 CXCL- TNF-α % cells /CD5+ cells 3 Gr+/F8- Losartan % of cells/cd+ cells 3 CD5+CD+ Losartan Fgure S ddtonal effects of losartan on the tumor mmune mcroenvronment. () Effect of losartan on cytokne expresson n PN and tumors n obese mce. Multplex proten revealed that losartan reduced the expresson of multple cytoknes ncludng IL-ß n PDCs (n=-7 tumors/group). () Wthn the CD5(+) populaton, losartan treatment tended to decrease the enrchment for GR(+)F8(-) cells (), and wthn CD(+) cells, the enrchment for CD5(+)CD(+) T regulatory cells (n= tumors/group). Error bars represent standard error of the mean. P values were determned by the Student t-test., P <.5,, P <.,, P <.. Frequency Fg. S. Dstrbuton of PDC patents accordng to ther MI. verage MI was 6.3 (Std. Dev. 5.66) % of stanng / tumor Fgure S 6 Ly6g.7 MI T Double+ Fgure S3 PN tumor tssue dpocytes Fgure S. Effect of obesty on the expresson of T, Ly6g, and T/Ly6g double postvty n PN tumors. % of Ly6G(+), T(+) or double postve (colocalzng) expresson n the total vable area of PN tumors (n=7-9 tumors/group). Quantfcaton of mmunofluorescent stanng. P values were determned by the Student t-test., P <.5. T αsm DPI Fgure S3. Representatve pcture of T expresson n cancer-assocated adpocytes (arrows) n PN tumors. Scale bar: μm.

9 Fgure S Cxcl- concentraton 3 T-KO INF-γ concentraton T-KO T-KO Hf-α C-IX LDHa ZE β-actn Proten expresson (normalzed to β-actn Hf-α C-IX LDHa T-KO Fgure S. ddtonal effects of T nhbton on obesty-aggravated mcroenvronment. () Effect of T ablaton on Cxcl- and INF-y expresson n PN tumors n obese mce. Multplex proten revealed that T deleton reduced the expresson of these cytoknes n PDCs (n=3- tumors/group). () Proten expresson of hypoxa markers and of ZE n PN tumors n WT and T-KO obese mce. (-) Each band represents an ndvdual tumor. (-) Quantfcaton normalzed to β-actn. ZE Fgure S5 p=.3 MI <5 MI >3 No Hypertenson Hypertenson Fgure S5. Prevalance of hyperteson n PDC patents. Percentage of patents that are hypertensve n each category of body mass ndex (MI). In obese patents, the proporton of patents that are hypertensve s ncreased. Data were obtaned usng the Ch-square test. P value s depcted.